Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1OC)[C:6]([CH2:12]Cl)=[N:7]2.[N:23]1[C:31]([NH2:32])=[C:30]2[C:26]([N:27]=[CH:28][NH:29]2)=[N:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:32][C:31]1[N:23]=[CH:24][N:25]=[C:26]2[C:30]=1[N:29]=[CH:28][N:27]2[CH2:12][C:6]1[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:3]=2)[C:4](=[O:22])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: COc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2cccc(Cl)c2c(=O)n1-c1ccccc1-c1ccccc1
Yield: 136.5 %

Procedure:
Prepared according to Procedure C using Intermediate 21 (400 mg, 1.05 mmol), adenine (155 mg, 1.15 mmol), K2CO3 (159 mg, 1.15 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 344 mg of a white solid (68%), mp 299.9-300.1° C. (discolors). 1H NMR (DMSO-d6) δ: 8.08 (s, 1H); 7.89 (s, 1H); 7.58-7.73 (m, 5H); 7.51 (d, J=7.9 Hz, 1H); 7.46 (d, J=7.5 Hz, 2H); 7.27-7.41 (m, 3H); 7.14-7.27 (m, 3H); 5.14 (d, J=17 Hz, 1H); 4.82 (d, J=17 Hz, 1H). 13C NMR (DMSO-d6) ppm: 159.6, 156.2, 152.8, 152.5, 150.0, 149.0, 141.7, 140.2, 137.7, 135.0, 133.3, 133.2, 131.8, 130.7, 130.1, 129.8, 129.5, 128.8, 128.6, 128.4, 127.1, 118.4, 117.6, 45.3. MS (ES): m/z 480.1 (M+). Anal. calcd. for C26H18ClN7O: C, 65.07; H, 3.78; Cl, 7.39; N, 20.43. Found: C, 64.77; H, 3.75; Cl, 7.43; N, 20.35.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[S:13]([Cl:17])(=[O:16])(=[O:15])[NH2:14].C(N(CC)CC)C>C(Cl)Cl>[ClH:17].[N:2]1[N:1]([C:6]2[CH:7]=[CH:8][C:9]([O:12][S:13](=[O:16])(=[O:15])[NH2:14])=[CH:10][CH:11]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Oc1ccc(-n2cncn2)cc1
Reactant: NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cl
Product: NS(=O)(=O)Oc1ccc(-n2cncn2)cc1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
4-(1H-1,2,4-triazol-1-yl)phenol (5.0 g, 0.031 mole) was suspended in methylene chloride (30 ml) and sulfamoyl chloride (7.13 g, 0.062 mole) added to the stirring mixture. Triethylamine (6.27 g, 0.062 mole) was added dropwise while maintaining the temperature between 25°-30° C. After the addition was complete the reaction was stirred for several hours at room temperature. HPLC analysis indicated the reaction had not gone to completion. The reaction was treated with an additional 0.031 mole of sulfamoyl chloride and triethylamine. The reaction stirred overnight at room temperature and was worked up after 1H NMR indicated reaction had gone to completion. The solvent was evaporated and the residue partitioned between ethyl acetate/acetonitrile (1:1)/aqueous sodium hydroxide, sodium bicarbonate (1:1). The organic layer was evaporated and the base isolated as an off-white powder (4.78 g, 64%). The crystals were dissolved in hot isopropyl alcohol, the solution cooled and the mixture filtered. The filtrate containing the base was evaporated to a residue, dissolved in methanol and a solution of anhydrous HCl/isopropyl alcohol added. White crystals precipitated out of solution as more isopropyl alcohol was added and methanol removed. The crystals were filtered, dried and analyzed (0.80 g, 0.0029 mole, 9%, mp 169°-173° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[CH3:12][NH:13][CH3:14].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:8]([N:13]([CH3:14])[CH3:12])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: Nc1cccnc1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ncccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To the mixture of 3-aminopicolinic acid (0.32 g, 2.32 mmol), dimethylamine hydrogen chloride (0.227 g, 1.2 eq), EDC (0.667 g, 1.5 eq), HOBt (0.376 g, 1.2 eq) in DMF (10 mL) was added DIEA (2.0 mL, 5.0 eq). The mixture was stirred at room temperature overnight. The crude was concentrated and dissolved in EtOAc. It was washed with saturated NaHCO3. The solvent was removed and the crude was purified by silica gel chromatography (0%˜20% MeOH/DCM) to obtain the desired product 3-amino-N,N-dimethylpicolinamide (0.375 g, isolated yield ˜98%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:14]Br>C(O)C>[Br:14][C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=1[NH2:8]
Reactant: BrBr
Reactant: Nc1ccc(Cl)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1nnc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
To a 250 mL round-bottomed flask was added 6-chloropyridazin-3-amine (3.92 g, 30.3 mmol), sodium bicarbonate (5.08 g, 60.5 mmol) and ethanol (20 mL). To the resulting solution, bromine (1.559 mL, 30.3 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 16 hours. The solution was filtered and then concentrated in vacuo. The residue was dissolved in water and the product extracted with ethyl acetate (3×). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-bromo-6-chloropyridazin-3-amine (4.5 g, 21.59 mmol, 71.3% yield). LC/MS, m/z 207.88 (M+1). HPLC Rt, 1.25 min. Waters Sunfire C18 column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.S(N(C1C=C(C(O)=O)C(N(S(=O)(=O)N)C2C=CC=CC=2)=CC=1C(O)=O)C1C=CC=CC=1)(=O)(=O)N>>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[C:8]([C:9](=[O:10])[C:4]=2[CH:3]=1)=[CH:12][C:13]1[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[C:16](=[O:18])[C:14]=1[CH:15]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: NS(=O)(=O)N(c1ccccc1)c1cc(C(=O)O)c(N(c2ccccc2)S(N)(=O)=O)cc1C(=O)O
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1

Procedure:
Pigmentary 2,9-dimethylquinacridone was prepared exactly as described in comparison Example 1 except that 10% by weight, relative to the 2,5-di(4-methylanilino)terephthalic acid, of 2,5-di(sulfamoylanilino)terephthalic acid (6.8 g) was included in the ring-closure reaction. 2,9-Dimethylquinacridone (59 g) was obtained as a magenta pigment.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH:8]([C:19]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=4)=O)[C:9]3=O)=[CH:4][C:3]1=2.[CH3:32][NH:33][NH2:34]>CO>[CH3:32][N:33]1[C:9]2[C:10]3[C:5]([CH2:6][CH2:7][C:8]=2[C:19]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:34]1)=[CH:4][C:3]1[C:2]([CH3:1])([CH3:31])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]=1[CH:11]=3
Reactant: COC(=O)c1ccc(C(=O)C2CCc3cc4c(cc3C2=O)C(C)(C)CCC4(C)C)cc1
Reactant: CNN
Solvent: CO
Product: COC(=O)c1ccc(-c2nn(C)c3c2CCc2cc4c(cc2-3)C(C)(C)CCC4(C)C)cc1
Yield: 65.1 %

Procedure:
4.5 g of methyl 4-(3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-1(2H)-anthracenon-2-ylcarbonyl)benzoate was suspended in 100 ml of methanol, followed by the addition thereto of 0.64 g of monomethylhydrazine. The obtained mixture was heated under reflux for 2 hours and cooled by allowing to stand to precipitate a solid. This solid was recovered by filtration and washed with methanol. 3.0 g of the title compound was obtained as a pale-yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][C:18]([O:20]CC)=O)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.O.[NH2:24][NH2:25]>C(O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][C:18]([NH:24][NH2:25])=[O:20])=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: NN
Reactant: CCOC(=O)CCc1ccc2c(cnn2C2CCCCO2)c1
Solvent: CCO
Solvent: O
Product: NNC(=O)CCc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 80 °C
Yield: 99.5 %

Procedure:
To a stirred solution of ethyl 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanoate (0.59 g, 1.951 mmol) in ethanol (5 mL) was added hydrazine hydrate (0.306 mL, 9.76 mmol) and the reaction was heated at 80° C. overnight. The solid which formed was filtered and dried to afford 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl) propanehydrazide (0.56 g, 82%), used without further purification. 1HNMR: 400 MHz, DMSO-d6: δ 1.58-1.59 (m, 2H), 1.92-1.96 (m, 1H), 1.97-2021.00 (m, 1H), 2.34-2.42 (m, 3H), 2.90-2.92 (m, 2H), 3.72-3.76 (m, 1H), 3.86-3.89 (m, 1H), 4.14 (s, 4H), 5.79-5.79 (m, 1H), 7.25-7.26 (m, 1H), 7.54 (s, 1H), 7.62 (d, J=8.80 Hz, 1H), 8.01 (s, 1H), 8.94 (s, 2H). LCMS: RT 0.64 min; LCMS (ES-API), m/z 205 (M-THP).
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](Cl)=[O:14].[Cl-].[Cl-].[Cl-].[Al+3]>C(=S)=S>[Br:1][C:2]1[C:6]([Br:7])=[CH:5][S:4][C:3]=1[C:13]([C:9]1[S:8][CH:12]=[CH:11][CH:10]=1)=[O:14]
Reactant: O=C(Cl)c1cccs1
Reactant: Brc1cscc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(c1cccs1)c1scc(Br)c1Br
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 30 g of 3,4-dibromothiophene and 13.5 mL of thiophene-2-carbonylchloride in 120 mL of carbon disulfide was added 16.5 g aluminum trichloride portionwise over 10 minutes. The mixture was stirred for 3 hours, poured into 900 g of ice-water and extracted with methylene chloride. The organic layer was washed with 1N NaOH (aq), water, and dried (MgSO4). Filtration and concentration of the filtrate, in vacuo, afforded an oil which crystallized upon trituration with n-chlorobutane to yield 32 g of the subject compound as an off-white solid, m.p. 105°-109° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:8].[Na+].[Cl:10][CH:11](O)[CH2:12][CH2:13][CH2:14]Cl>O>[Cl:10][CH2:11][CH2:12][CH:13]([OH:8])[CH2:14][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: [OH-]
Reactant: OC(Cl)CCCCl
Agent: [Na+]
Solvent: O
Product: OC(CCCl)COc1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a mixture which contained 282 g. (3 moles) of phenol, one liter of water and 300 ml. of 50% sodium hydroxide was added slowly with stirring at 60° C. 443.36 g. (3.1 moles) of 1,4-dichlorobutanol. Stirring was continued at 60° C. for 16 hr. The resulting mixture was extracted twice with one liter of ether and the combined ether extracts were washed with water to neutrality and dried overnight over sodium sulfate. The dried ether mixture was concentrated to dryness under reduced pressure. The residue was distilled and yielded 435 g. of product which was collected at 135°-138° C./0.05 mm. The product solidified and was recrystallized using pet. ether (60°-110° C.) to give a white crystalline solid which melted at 52°-54° C.
Reaction SMILES: [C:1]([O:4][CH:5](SC)[C:6](=[O:19])[C@@H:7]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]([CH3:10])[CH3:9])(=[O:3])[CH3:2].CCO.[BH4-].[Na+].Cl>O.CCOC(C)=O>[C:1]([O:4][CH2:5][CH:6]([OH:19])[C@@H:7]([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH:8]([CH3:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CSC(OC(C)=O)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(=O)OCC(O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suitable reactor was added 3e (1.32 g, 1.0 equiv) and EtOH (26 mL) at 20-30° C. under N2. The mixture was cooled to −25 to −15° C., and NaBH4 (117.4 mg, 0.8 equiv) in H2O (2.6 mL) was added at below −15° C. The reaction mixture was warmed to −5-5° C. and stirred for 1 hr. The reaction was deemed completed as determined by TLC. 1N HCl aqueous solution (13 mL) was added at below 10° C., and the mixture was warmed to 20-30° C. EtOAc (160 mL) was added at 20-30° C., and the mixture was stirred at this temperature for 30 min. The separated organic portion was concentrated at 40-50° C. under reduced pressure to afford crude 4e. The diastereomeric ratio of crude 4e was determined to be 78/22 by HPLC analysis. The residue was purified by flash column chromatography (EtOAc/n-heptane=1/2) to give a diastereomeric mixture of 4e (0.92 g, 81% yield) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([NH:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[C:26]([F:54])=[C:27]([C@@H:31]2[C@:35]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=3[F:45])([C:36]#[N:37])[C@H:34]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[NH:33][C@H:32]2[C:51](O)=[O:52])[CH:28]=[CH:29][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:13][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:51]([C@@H:32]2[C@@H:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[C:26]=3[F:54])[C@@:35]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=3[F:45])([C:36]#[N:37])[C@@H:34]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[NH:33]2)=[O:52])=[CH:7][CH:6]=1)([C:9](=[O:10])[NH:11][CH3:12])[CH3:14]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CNC(=O)C(C)(C)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(C)(C)c1ccc(NC(=O)[C@H]2N[C@H](CC(C)(C)C)[C@@](C#N)(c3ccc(Cl)cc3F)[C@@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
Reagent 2-(4-amino-phenyl)-N-methyl-isobutyramide (130 mg, 0.676 mmol) was dissolved in dichloromethane (4 mL) then iPr2NEt (0.375 mL, 2.15 mmol) was added and stirred at 25° C. In three portions chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.214 mmol) and 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 106 mg, 0.278 mmol) was added in 30 min intervals. The reaction mixture was stirred at 25° C. for 5 hours, complete by LCMS. The mixture was then diluted with CH2Cl2 and washed with water. The organic phase was separated, then concentrated under reduced pressure. The compound was purified by RP-HPLC (30-95% acetonitrile/water) to afford chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1-methyl-1-methylcarbamoyl-ethyl)-phenyl]-amide as an off-white solid (56 mg, 40.8%) HRMS (ES+) m/z Calcd for C34H36Cl2F2N4O2+H [(M+H)+]: 641.2256. found: 641.2256.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[NH2:5].[CH3:18][CH:19]([C:25]([CH3:27])=O)[C:20](OCC)=[O:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.ClC1C(C(=O)C2C=CC(Cl)=CC=2)=CC=C2C=1C(O)=C(C)C(C)=N2>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([C:20]([OH:21])=[C:19]([CH3:18])[C:25]([CH3:27])=[N:5]2)=[CH:7][C:8]=1[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: Nc1ccc(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1nc2ccc(C(=O)c3ccc(Cl)cc3)c(Cl)c2c(O)c1C
Solvent: Cc1ccccc1C
Product: Cc1nc2cc(Cl)c(C(=O)c3ccc(Cl)cc3)cc2c(O)c1C
Yield: 77 %

Procedure:
A solution of 2.7 g of 3-chloro-4-(4-chlorobenzoyl)aniline, 2.4 g of ethyl 2-methylacetoacetate, and 0.3 g of p-toluenesulfonic acid dissolved in 100 mL of xylene was heated under reflux for 31 hr. This reaction solution was cooled, and the precipitated crystals were collected by filtration and were washed with n-hexane to give 2.68 g of a mixture of 5-chloro-6-(4-chlorobenzoyl)-4-hydroxy-2,3-dimethyl-quinoline with 7-chloro-6-(4-chlorobenzoyl)-4-hydroxy-2,3-dimethyl-quinoline (yield 77%). The crystals of the mixture thus obtained were stirred in 40 mL of acetic anhydride with heating at 120 to 125° C. for one hr. The reaction solution was concentrated, and the crude product was then purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) to give 1.0 g of 4-acetoxy-5-chloro-6-(4-chlorobenzoyl)-2,3-dimethyl-quinoline (yield 32.6%) and 0.47 g of 4-acetoxy-7-chloro-6-(4-chlorobenzoyl)-2,3-dimethyl-quinoline (yield 15.6%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C:13]([Cl:22])=[N:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH2:26][CH2:25]1>>[ClH:22].[ClH:22].[CH2:1]([O:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C:13]([NH:23][CH:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=3)[CH2:28][CH2:29]2)=[N:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(COCc3ccccc3)nnc(Cl)c2c1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1ccc2c(COCc3ccccc3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1
Product: Cl

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 4-benzyloxymethyl-1-chloro-7-methoxyphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].[Br:13]Br>>[Br:13][C:11]1[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: BrBr
Product: O=[N+]([O-])c1cc(Br)c2c(c1)CCN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 131.5 %

Procedure:
To a solution of 5-nitroindoline (from Aldrich, 2.0 g, 12.2 mmol) in 15 mL of ACOH was added Br2 (1.0 mL, 19.4 mmol) in a portion and the resulting solution was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo, yielding a yellow solid (3.9 g, >95%) of the desired product as a HBr salt, which was subjected to the following reaction without further purification.
Reaction SMILES: C[Mg]Br.[C:4]1([CH3:10])[CH:9]=C[CH:7]=[CH:6][CH:5]=1.C1C[O:14]CC1.C(C([C@H]1C[O:30][C:29](=[O:32])[NH:28]1)C([O-])=O)C1C=CC=CC=1>C(O)(=O)C.O>[OH:14][C:4]([CH3:10])([CH3:9])[CH2:5][C@H:6]1[CH2:7][O:32][C:29](=[O:30])[NH:28]1
Reactant: C1CCOC1
Reactant: O=C1N[C@@H](C(Cc2ccccc2)C(=O)[O-])CO1
Reactant: Cc1ccccc1
Agent: C[Mg]Br
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(O)C[C@H]1COC(=O)N1
Reaction time: 2 h

Procedure:
Methylmagnesium bromide (227 mL of 3M solution in diethyl ether) was added to a mixture of toluene (340 mL) and THF (340 mL) at −20° C. A warm THF solution (170 mL) of the ester from Step 2 (40 g) was then added dropwise maintaining the temperature below −10° C. The mixture was aged for 2 hours and was then slowly added to a mixture of water (1000 mL) and acetic acid (200 mL) and the resultant mixture was stirred for 2 hours at room temperature. The aqueous layer was separated and the organic layer was extracted with water (2×200 mL). The product was extracted from the combined aqueous layers using dichloromethane and a continuous extractor. The dichloromethane extract was evaporated to dryness using heptane as a co-solvent to azeotrope off the acetic acid. The residue was purified by chromatography on SiO2 using ethanol and dichloromethane (1:30) to yield (4S)-4-(2-hydroxy-2-methylpropyl)-1,3-oxazolidin-2-one.
Reaction SMILES: [CH3:1]C1C=CC(C2C=NN(C)C=2)=C(C=1)C(OC)=O.Br[C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[N:24][C:25]([NH:29][CH2:30][C@@H:31]3[C@H:36]([CH3:37])[CH2:35][CH2:34][CH2:33][N:32]3[C:38]([C:40]3[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=3[N:47]3[N:51]=[CH:50][CH:49]=[N:48]3)=[O:39])=[N:26]2)=[CH:21][CH:20]=1.CB1OB(C)OB(C)O1>>[CH3:37][C@@H:36]1[CH2:35][CH2:34][CH2:33][N:32]([C:38]([C:40]2[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=2[N:47]2[N:48]=[CH:49][CH:50]=[N:51]2)=[O:39])[C@@H:31]1[CH2:30][NH:29][C:25]1[N:24]=[CH:23][C:22]2[C:27](=[CH:28][C:19]([CH3:1])=[CH:20][CH:21]=2)[N:26]=1
Reactant: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3ccc(Br)cc3n2)c1
Agent: CB1OB(C)OB(C)O1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3ccc(C)cc3n2)c1

Procedure:
The title compound was prepared following the same general protocol as described for methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate in Example A1, using ((2S,3R)-2-(((7-bromoquinazolin-2-yl)amino)methyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane. ESI-MS (m/z): 456 [M+1]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>CS(C)=O.O>[N:17]([CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1)=[N+:18]=[N-:19]
Reactant: COC(=O)c1ccc(CBr)c2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(CN=[N+]=[N-])c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a solution of methyl 4-(bromomethyl)-1-naphthoate (30 g, 0.107 mol) in anhydrous DMSO (300 mL) was added NaN3 portion wise (14 g, 0.215 mol) at 0° C. and stirred at rt for 16 h. Then the reaction mixture was diluted with water (500 mL), extracted with EtOAc (2×250 mL), washed with water, brine and dried over MgSO4. The solvent was removed under vacuum to give methyl 4-(azidomethyl)-1-naphthoate (20 g, 77%).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([I:9])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:10].[C-:11]#[N:12].[K+]>CCO.O>[Cl:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([I:9])[C:3]=1[CH2:2][C:11]#[N:12]
Reactant: [C-]#N
Reactant: Clc1cccc(I)c1CBr
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1c(Cl)cccc1I
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A mixture of 2-(bromomethyl)-1-chloro-3-iodobenzene (14 g, 42 mmol) in 100 mL EtOH was treated with a solution of potassium cyanide (3.6 mL, 84 mmol) in 40 mL water. The mixture was refluxed for 2.5 hours. The mixture was cooled to room temperature and then concentrated. The residue was diluted with 200 mL EtOAc, washed with water (2×50 mL), saturated NaCl (50 mL), dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (20% EtOAc/hexane) to give 10.18 g pale yellow solid. MS m/e: (M−1)− 276.
Reaction SMILES: C12[N:8]([C:9]3C=N[C:16]4[C:11](=[CH:12]C=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([N:28]1[CH2:34][CH:33]2[CH:30]([CH2:31][NH:32]2)[CH2:29]1)=[O:27].ClC1N=C(C)C=C(C)N=1>>[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([N:28]1[CH2:34][CH:33]2[CH:30]([CH2:31][N:32]2[C:9]2[N:8]=[C:15]([CH3:14])[CH:16]=[C:11]([CH3:12])[N:10]=2)[CH2:29]1)=[O:27]
Reactant: O=C(c1ccccc1Br)N1CC2CNC2C1
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Agent: Cc1cc(C)nc(Cl)n1
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccccc4Br)CC32)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 23 and 2-chloro-4,6-dimethylpyrimidine. MS (ESI) mass calcd. for C18H19BrN4O, 387.28; m/z found, 389.1 [M+H]+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:15])[F:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[CH2:33][C@H:32]([CH3:34])[NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:31]1[C@@H:32]([CH3:34])[CH2:33][C@H:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[CH:9]=[C:10]([CH:13]([F:14])[F:15])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:30]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CN[C@@H](C)C1
Agent: Cl
Product: CC(=O)N1C[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-N-[(3S*,5S*)-5-methylpyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f66) and commercially available acetyl chloride the title compound is obtained as colorless solid.