Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([CH3:11])[C:3]=1[CH:12]1[C:16](=[O:17])[CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:14][C:13]1=[O:25].C(N(C(C)C)C(C)C)C.Cl[C:36]([S:38][CH:39]([CH3:41])[CH3:40])=[O:37]>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[C:16](=[O:17])[CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:14][C:13]=1[O:25][C:36]([S:38][CH:39]([CH3:41])[CH3:40])=[O:37]
Reactant: CC(C)SC(=O)Cl
Reactant: CC#Cc1cc(C)c(C2C(=O)CC(Cc3ccccn3)C2=O)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC#Cc1cc(C)c(C2=C(OC(=O)SC(C)C)CC(Cc3ccccn3)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
To a solution of the 2-(2,6-dimethyl-4-prop-1-ynyl-phenyl)-4-(2-pyridylmethyl)cyclopentane-1,3-dione (0.100 g, 0.302 mmol) in dichloromethane (3.02 mL) was added N-ethyl-N-isopropyl-propan-2-amine (1.51 mmol, 0.265 mL). The reaction was then cooled in the freezer for 30 minutes before addition of S-isopropyl chlorothioformate (0.075 ml, 0.603 mmol), and then the reaction mixture was stirred overnight at room temperature. The reaction was then washed with water, dried and reduced in vacuo. The crude product was then purified by column chromatography, eluting with acetonitrile and dichloromethane, to give the desired product (23 mg, 18%). The product was characterised by HPLC, as follows.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:37][CH2:36][N:35]4[CH2:38][CH2:39][NH:40][CH2:41][CH:34]4[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[C:53](Cl)(=[O:55])[CH3:54]>ClCCl>[C:53]([N:40]1[CH2:39][CH2:38][N:35]2[CH2:36][CH2:37][N:32]([C:21]3[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]4[CH:4]=[C:3]([C:2]([F:44])([F:1])[F:45])[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=4)([CH3:43])[CH3:42])=[C:23]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[CH3:31])[CH:22]=3)[CH2:33][CH:34]2[CH2:41]1)(=[O:55])[CH3:54]
Reactant: CC(=O)Cl
Reactant: Cc1cc(F)ccc1-c1cc(N2CCN3CCNCC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN2CCN(c3cc(-c4ccc(F)cc4C)c(N(C)C(=O)C(C)(C)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)cn3)CC2C1
Reaction time: 2 h

Procedure:
To a solution of crude 2-[3,5-bis(trifluoromethyl)phenyl]-N-[4-(4-fluoro-2-methyl phenyl)-6-(octahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)-3-pyridinyl]-N,2-dimethylpropanamide (prepared with an analogous procedure to that described for D80, 89 mg, 0.14 mmol) in 5 mL of dichloromethane were added at 0° C. triethylamine (197 μL, 1.41 mmol) and acetyl chloride (75 μL, 1.0 mmol). The reaction was left at room temperature for 2 h. It was diluted with dichloromethane, extracted with sat NaHCO3 solution, the organics dried (Na2SO4), and the solvent was removed. The product was purified by flash chromatography (silica, cyclohexane:EtOAc 50:50 to EtOAc). Obtained 60 mg.
Reaction SMILES: C([N:8]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:23]=2)[C:11]2[C:12]3[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15][C:13]=3[NH:14][C:10]=2[C:9]1=[O:33])C1C=CC=CC=1>C(OC(=O)C)(=O)C>[CH2:31]([S:28]([C:24]1[CH:23]=[C:22]([C:20]2[C:11]3[C:12]4[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15][C:13]=4[NH:14][C:10]=3[C:9](=[O:33])[NH:8][CH:21]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:29])=[O:30])[CH3:32]
Reactant: CCS(=O)(=O)c1cccc(-c2cn(Cc3ccccc3)c(=O)c3[nH]c4ncc(C)cc4c23)c1
Solvent: CC(=O)OC(C)=O
Product: CCS(=O)(=O)c1cccc(-c2c[nH]c(=O)c3[nH]c4ncc(C)cc4c23)c1
Reaction time: 4 h
Yield: 23.6 %

Procedure:
Compound 30 (24 mg, 0.053 mmol) was stirred in acetic anhydride (2 mL) at reflux overnight. Solvent was removed in vacuo, and the residue was subjected to hydrogenation with 20% palladium hydroxide on carbon (25 mg) in acetic acid (5 mL) under a balloon of hydrogen at 36° C. for 4 h. The reaction was filtered through Celite and concentrated in vacuo. Purification by prep HPLC gave 4.6 mg (24%) of the title compound as a white solid. 1H NMR (400 MHz, MeOD-d4/CDCl3): δ 8.41 (br s, 1H), 8.12 (s, 1H), 8.02 (d, 1H, J=8.0 Hz), 7.92 (d, 1H, J=8.0 Hz), 7.80 (t, 1H, J=8.0 Hz), 7.67 (s, 1H), 7.30 (br s, 1H), 7.14 (s, 1H), 3.25 (q, 2H, J=7.2 Hz), 2.35 (s, 3H), 1.31 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C19H17N3O3S, 368; found 368.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[C:8]([N+:14]([O-])=O)[C:7]=1[CH3:17])(=[O:3])[CH3:2].[Cl-].[NH4+]>CO.[Zn]>[C:1]([O:4][CH2:5][C:6]1[C:7]([CH3:17])=[C:8]([C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])[NH2:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(C)cc(C)c([N+](=O)[O-])c1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(=O)OCc1c(C)cc(C)c(N)c1C
Yield: 72.8 %

Procedure:
To a solution of 1-acetoxymethyl-3-nitro-2,4,6-trimethybenzene (6.0 g, 25.2 mmol) in methanol (100 mL) were sequentially added ammonium chloride (2.7 g in 25 mL of water), zinc powder (11 g). The exothermic reaction was vigorously stirred until it was back to RT (2 h). To work up the crude mixture was filtered off and the cake was washed with methanol. The methanolic solutions were concentrated to a volume of 20 mL, added 1 N HCl (300 mL). The insoluble material was removed by filtration, the solution was basified with solid NaHCO3. The semicrystalline precipitate was taken into ethyl acetate. The extract was concentrated and the residual product purified by means of column chromatography (25% ethyl acetate/hexane) to give 3-Acetoxymethyl-2,4,6-trimethylaniline as a pink oil (3.8 g, 75%).
Reaction SMILES: C[O-].[Na+].[C:4]([OH:12])(=[S:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[CH2:14][C:15]#[N:16]>C1COCC1.CCOCC>[C:4]([S:11][CH2:14][C:15]#[N:16])(=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OC(=S)c1ccccc1
Reactant: N#CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CCSC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Sodium methoxide (5.13 g; 0.095 mol) is added with stirring to an ice cold solution of thiobenzoic acid (13.8 g; 0.095 mol) in THF (100 ml). A yellow slurry forms. Next, chloroacetonitrile (6.45 ml; 0.10 mol) is added, and the reaction mixture stirred overnight at room temperature. It is then filtered, and the filtrate concentrated in vacuo to yield a yellow oil. This oil is dissolved in ether, the solution washed with saturated sodium bicarbonate solution, saturated salt solution, dried over sodium sulfate and concentrated in vacuo. The residual oil is distilled (boiling point 105°-106° C. at 10.5 mm) to afford 12.8 g (76%) of title product, a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C:27](O)=[O:28])=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:14]=4[N:15]=3)[N:7]([CH3:25])[C:6]=2[CH:26]=1.C(O)(=O)C.[CH3:34][N:35]([CH3:40])[C:36](=[O:39])[CH2:37][NH2:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:34][N:35]([CH3:40])[C:36]([CH2:37][NH:38][C:27]([C:3]1[C:2]([F:1])=[CH:26][C:6]2[N:7]([CH3:25])[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:22])([F:23])[F:24])[CH:17]=[CH:16][C:14]=4[N:15]=3)=[N:9][C:5]=2[CH:4]=1)=[O:28])=[O:39]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)c(F)cc21
Reactant: CN(C)C(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CNC(=O)c1cc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2cc1F
Yield: 35.6 %

Procedure:
6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (32 mg) was prepared by following General Procedure F starting from 6-fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), glycine dimethylamide acetate (32 mg), HBTU (80 mg), and DIEA (46 uL). LC/MS: m/z 511.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (bs, 1H), 8.19-8.00 (m, 2H), 7.93 (s, 1H), 7.74 (d, 1H), 7.54 (d, 1H), 7.36 (d, 1H), 4.18 (d, 2H), 3.61 (bs, 3H), 3.01 (s, 3H), 2.89 (s, 3H).
Reaction SMILES: N[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:11]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.S(=O)(=O)(O)O>O>[CH:8]1[CH:7]=[CH:6][C:5]2[CH2:4][CH2:3][N:2]3[C:10]=2[C:9]=1[C:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=13
Reactant: O=C1CCCCCC1
Reactant: NN1CCc2ccccc21
Agent: O=S(=O)(O)O
Solvent: O
Product: c1cc2c3c(c1)c1c(n3CC2)CCCCC1
Yield: 29.9 %

Procedure:
Following the procedure of Example 1, step 1, indoline (20 g, 170 mmol), sodium nitrite (14 g, 200 mmol), concentrated hydrochloric acid (30 mL) in water (70 mL) and ether (120 mL) provided 1-nitroindoline (31 g), which was reduced with zinc dust (˜50 g) in acetic acid (500 mL) to provide 1-aminoindoline (29 g). A mixture of 1-aminoindoline (17 g, 130 mmol), cycloheptanone (15 mL, 130 mmol), and concentrated sulfuric acid (20 mL) in water (180 mL) provided 8.2 g of 4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole. MS (ESI) m/z 212.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([NH:10][CH:11]([CH:14]=[O:15])[CH2:12][CH3:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:19]=1[CH3:26].CC(=CC)C.[O-:33]Cl=O.[Na+]>>[CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([NH:10][CH:11]([C:14]([OH:33])=[O:15])[CH2:12][CH3:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:19]([CH3:26])=[CH:20][C:21]([Cl:25])=[CH:22][C:23]=1[CH3:24]
Reactant: CCC(C=O)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Product: CCC(Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-formyl-propylamino)-6-methyl-nicotinic acid methyl ester, 2-methyl-2-butene, excess NaClO2, and NaH2PO4 was stirred at rt for 15 min. The mixture was quenched with sat. sodium bicarbonate and extracted with hexane. The aqueous layer was acidified to pH 4 and extracted twice with diethyl ether. The organic layer was separated, dried and concentrated to give the title compound. The crude material was purified by silica gel column chromatography to give the desired product as a white crystal after recrystallization. Anal. For C20H23N2O5Cl calc., C, 59.04; H, 5.70; N, 6.89; found C, 59.29; H, 5.73; N, 6.83.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:6]=[CH:5][N:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Brc1ccn(-c2ccccn2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1cccc(-c2ccn(-c3ccccn3)c2)c1
Temperature: 84 °C

Procedure:
2-(3-Bromo-1H-pyrrol-1-yl)pyridine (1.34 g, 2 mmol), 3-chlorophenylboronic acid (0.62 g, 4 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol) and potassium carbonate (560 mg, 4 mmol) were dissolved in a mixture of DME (18 mL) and H2O (2 mL) and degassed for 15 min with Ar (g). The reaction mixture was then heated at 84° C. for 18 h. At this time, a further 0.25 eq. of 3-chlorophenylboronic acid (0.16 g, 1 mmol) was added and heating was continued. After a total of 42 h, the reaction mixture was cooled to rt, H2O (40 mL) and EtOAc (40 mL) were added and the reaction mixture shaken, the EtOAc layer was separated and the aqueous layer shaken with EtOAc (2×30 mL). The combined organic layers were dried over Na2SO4 and concentrated to a yellow oil. This was purified by liquid chromatography on silica gel eluting with EtOAc:hexane (3:7) to afford a white solid that was further purified by preparative HPLC to afford 2-[3-(3-chlorophenyl)-1H-pyrrol-1-yl]pyridine as a white solid. 1H NMR (CD3Cl, 300 MHz) δ 8.52-8.54 (1H, m), 7.61 (1H, ddd), 7.35-7.37 (1H, m), 7.28 (1H, s), 7.15-7.24 (3H, m), 6.99 (1H, ddd), 6.86 (1H, d), 6.47-6.48 (1H, m), 6.41 (1H, dd).). MS (ESI) 255 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].Cl.[NH2:15][CH:16]([P:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[C:17]([O:19][CH3:20])=[O:18].CN1CCOCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:26]([O:25][P:21]([O:22][CH2:23][CH3:24])[CH:16]([NH:15][C:5](=[O:6])[C:4]1[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:8]=1[O:12][CH3:13])[C:17]([O:19][CH3:20])=[O:18])[CH3:27]
Reactant: CCOP(OCC)C(N)C(=O)OC
Reactant: COc1cccc(OC)c1C(=O)Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOP(OCC)C(NC(=O)c1c(OC)cccc1OC)C(=O)OC
Reaction time: 8 h

Procedure:
2,6-Dimethoxybenzoyl chloride (1.28 g, 6.42 mmol) was added to a mixture of methyl 2-amino-2-(diethoxyphosphino)acetate hydrochloride [1.5 g, 6.11 mmol, prepared by the method of Y. Nasukawa, et al, J. Org. Chem, (1992) 57, 5453] and NMM (1.5 ml, 13.44 mmol) in CH2Cl2 (30 ml). The mixture was stirred overnight at room temperatue then poured into 10% citric acid. The mixture was extracted with CH2Cl2 (×2) and the combined organic extracts washed with sodium hydrogen carbonate solution (×2) and brine, dried (MgSO4) and evaporated in vacuo to give a brown solid (1.62 g). δH (DMSO-d6) 8.82 (1H, dd, J 9.1, 2.5 Hz), 7.29 (1H, t, J 8.4 Hz), 6.65 (2H, d, J 8.4 Hz), 5.20 (1H, dd, J 20.0, 9.2 Hz), 4.15-4.03 (4H, m), 3.72 (3H, s), 3.71 (6H, s), 1.39-1.20 (6H, m); m/z (ESI) 390 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH2:23][CH3:24])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[O:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34]>>[CH2:23]([C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:31]3[CH2:32][CH2:33][O:29][C:30]3=[O:34])=[CH:3][C:4]=2[S:25]([CH3:28])(=[O:27])=[O:26])=[O:9])[CH2:11][CH2:12]1)[CH3:24]
Reactant: O=C1NCCO1
Reactant: CCc1cc(C)ccc1N1CCN(C(=O)c2ccc(Br)cc2S(C)(=O)=O)CC1
Product: CCc1cc(C)ccc1N1CCN(C(=O)c2ccc(N3CCOC3=O)cc2S(C)(=O)=O)CC1
Yield: 1.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(2-ethyl-4-methylphenyl)piperazin-1-yl]methanone (1.8 g) described in Preparation Example 15 and oxazolidin-2-one (418 mg), the title compound (22 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1.C([O-])([O-])=O.[K+].[K+].CN(C)CC(O)=O.N.O>[Cu]I.CCOC(C)=O.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17]([N:38]3[CH:42]=[CH:41][N:40]=[CH:39]3)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CN1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: N
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-n3ccnc3)cn2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 33.8 %

Procedure:
A 25 ml round-bottom tube is charged with (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (480 mg, 0.8 mmol), imidazole (82 mg, 1.2 mmol), CuI (152 mg, 0.8 mmol), K2CO3 (221 mg, 1.3 mmol), N,N-dimethyl glycine (82 mg, 0.8 mmol), and DMSO (4 ml). Then the tube is sealed and heated to 110 degree for 18 hours. After cooling to rt, saturated NH3/H2O and EtOAc are added and then filtered through Celite pad. The solution is extracted with EtOAc and organic layer is dried over MgSO4. Removal of solvent under reduced pressure and purification with reverse phase column give product (163 mg, 0.27 mmol, 35%). ESI-MS m/z: 585 [M]+, Retention time 2.07 min (condition A).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])N.[CH3:13][C:14](=O)[CH2:15][CH3:16].Cl>C(O)(=O)C.O>[CH3:13][C:14]1[NH:2][C:4]2[C:12]([C:15]=1[CH3:16])=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7]
Reactant: CCC(C)=O
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]c2c(C(=O)O)cccc2c1C
Temperature: 100 °C

Procedure:
To a suspension of 2-hydrazinobenzoic acid hydrochloride (2.0 g) in acetic acid (8 ml) was added dropwise a solution of 2-butanone (0.9 ml) in acetic acid (2 ml), and the resultant mixture was heated at 80° C. for one hour. After 6N-hydrochloric acid (8 ml) was added to the reaction mixture, the mixture was heated at 100° C. for 5 hours. The mixture was diluted with water (18 ml), and allowed to cool to 40° C. The resultant precipitate was collected by filtration, washed with a small amount of diisopropyl ether and dried in vacuo to give 2,3-dimethyl-1H-indole-7-carboxylic acid (0.78 g).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH2:29]([N:31]([CH2:37][CH3:38])[CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)[CH3:30]>>[CH2:29]([N:31]([CH2:37][CH3:38])[CH:32]1[CH2:36][CH2:35][N:34]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:33]1)[CH3:30]
Reactant: CCN(CC)C1CCNC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: CCN(CC)C1CCN(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)C1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with N,N-diethylpyrrolidin-3-amine via General Procedure E to give 27.8 mg of 296 following reverse phase purification. MS (Q1) 504.3 (M)+
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[C:22]1([CH3:30])[C:23]([CH:28]=O)=[CH:24][CH:25]=[CH:26][CH:27]=1>C1(C)C=CC=CC=1>[CH3:30][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=[N:15][C:13]1[C:12]2[C:7]([N:6]=[C:5]3[C:14]=1[CH2:1][CH2:2][CH2:3][CH2:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: Cc1ccccc1C=O
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: Cc1ccccc1C=Nc1c2c(nc3ccccc13)CCCC2

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (4.0 g) was suspended in 400 ml of toluene to which morpholine (3.5 g) and o-tolualdehyde (3.0 g) were successively added. The reaction mixture was refluxed overnight and then an additional 1.5 g of aldehyde was added. Reflux was continued for an additional six (6) hours and then the reaction mixture was concentrated and purified by flash chromatography (CH2Cl2, then 20% EtOAc/CH2Cl2). Fractions containing the pure product were concentrated and recrystallized from benzene/pentane to give 3.32 g of analytically pure product, m.p. 160°-162° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10]C)=[O:9].[OH-].[Na+].Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1sccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccsc1C(=O)O
Temperature: 75 °C
Reaction time: 18 h
Yield: 100.3 %

Procedure:
To a solution of methyl 3-methoxythiophene carboxylate (2.0 g, 11.6 mmol) in 20 mL of THF at room temperature was added dropwise a 1.0 M sodium hydroxide aqueous solution (17.0 mL, 17.0 mmol). After addition, the mixture was heated to 75° C. (oil bath temperature) and continued for 18 h. The mixture was cooled to room temperature, treated with a 1.0 M hydrochloride aqueous solution until pH approximately being 2. The acidified mixture was extracted with 100 mL of CH2Cl2—CH3CN (1:1, v/v), 50 mL of CH2Cl2, and 50 mL of CH3CN. The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure to a solid, which was further dried on high vacuum, yielding 1.84 g (100%) of 3-methoxythiophene carboxylic acid (MH+=159.0).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:10]1([N:13]2[C:21]3[C:16](=[CH:17][C:18]([CH2:22][NH:23][S:24]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:28]=4[CH3:37])(=[O:26])=[O:25])=[CH:19][CH:20]=3)[CH:15]=[N:14]2)[CH2:12][CH2:11]1>>[CH:10]1([N:13]2[C:21]3[C:16](=[CH:17][C:18]([CH2:22][N:23]([C:3]4[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=4)[S:24]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:28]=4[CH3:37])(=[O:26])=[O:25])=[CH:19][CH:20]=3)[CH:15]=[N:14]2)[CH2:12][CH2:11]1
Reactant: Fc1ncc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C3CC3)c2)c(C)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C3CC3)c2)c2ncc(Cl)cc2Cl)c(C)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and methyl 4-(N-((1-cyclopropyl-1H-indazol-5-yl)methyl)sulfamoyl)-3-methylbenzoate (step-2 of Example 33).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][Cl:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:12][CH2:11][CH2:10][CH2:9][S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: Sc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCSc1ccncc1
Yield: 86.9 %

Procedure:
A mixture of 4-mercaptopyridine (5.0 g), 1-bromo-3-chloropropane (14.2 g), and anhydrous potassium carbonate in 250 mL acetone is refluxed under nitrogen for 1 hour. The mixture is cooled, filtered and concentrated. The residue is taken up into diethyl ether and washed with brine, dried over magnesium sulfate and evaporated in vacuo. The crude product is purified by column chromatography (silica; hexane: ethyl acetate, 50:50) to give the title compound (7.34 g) as a colorless oil which is used directly in further transformations.
Reaction SMILES: [P:1]([O-:23])([O-:22])([O:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:2].[OH-].[K+:25].[CH2:26]([CH:28]1[O:30][CH2:29]1)[Cl:27]>>[P:1]([O-:22])([O:23][CH2:29][CH:28]([OH:30])[CH2:26][Cl:27])([O:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:2].[K+:25]
Reactant: ClCC1CO1
Reactant: CCCCCCCCCCCCCCCCC=COP(=O)([O-])[O-]
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCC=COP(=O)([O-])OCC(O)CCl
Temperature: 80 °C
Reaction time: 6 h
Yield: 67.8 %

Procedure:
20 g (0.052 moles) of monooctadecenyl phosphate having a purity of 90% (AV1=165.0, AV2=323.2) was charged into a reactor, to which 58.8 ml of 1N potassium hydroxide aqueous solution was added and agitated at 80° C. to obtain uniform solution, at which the acid value of the reaction system was 40.2. While keeping the reaction system at 80° C., 24.1 g (0.26 moles) of epichlorohydrin was gradually dropped, followed by agitation at the temperature for 6 hours. The acid value of the reaction system was approximately zero, revealing that the reaction rate of the phosphoric monoester was almost 100%. The resulting product was collected by HPLC and the solvent was distilled off under reduced pressure to obtain 16.9 g (yield 67.8%) of potassium octadecenyl 2-hydroxy-3-chloropropyl phosphate.