Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1Br.[Li]C(C)(C)C.[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.CON(C)[C:31](=[O:41])[CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]>C1COCC1.ClCCl>[CH3:16][O:17][C:18]1[C:27]([C:31](=[O:41])[CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reactant: COc1ccc2ccccc2n1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1nc2ccccc2cc1C(=O)CNC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of mesityl bromide (4 eq.) in THF (1.7 M) cooled to −78° C. was added a solution of tBuLi in THF (8 eq., 1.7 M) dropwise. The mixture was left stirring at −78° C. for 1 h. Mixture was then allowed to reach 0° C. and a solution of 2-methoxyquinoline (3 eq.) in THF (0.32 M) was added dropwise over 10 min. The resulting mixture was aged at 0° C. for 1 h, then cooled to −78° C. and added dropwise with a solution of tert-butyl (2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (1 eq.) in THF (0.22 M). The reaction mixture was stirred at −78° C. for 30 min, then left at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with sat. aq. NaHCO3, dried over Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography (SiO2, Petroleum ether/EtOAc, from 5% to 40% EtOAc). Pooled fractions were concentrated under vacuum to give the title compound. MS (ES+) C17H20N2O4: 317 (M+H)+.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3]1.C(N(CC)CC)C.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[S:2]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:3]1
Reactant: NCCc1ccsc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCc1ccsc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
2-(Thiophen-3-yl)ethanamine hydrochloride (3 g, 18 mmol) was taken in THF (40 mL) and treated with triethylamine (9.92 mL, 71.2 mmol). The reaction was cooled down to 0° C. and benzoyl chloride (2.55 mL, 21.9 mmol), diluted with THF was added dropwise to the reaction. The reaction was stirred for 3 h and the volatiles removed in vacuo. The residue was dissolved in ethyl acetate and washed with an aqueous saturated solution of sodium bicarbonate, water and brine. The organic solution was dried with sodium sulfate and purified by flash chromatography using a gradient of 25 to 70% ethyl acetate in hexanes to afford an off-white solid (4 g). MS (M+H)+ 232.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][C:31]([OH:33])=O)[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[NH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][C:31]([N:59]4[CH2:64][CH2:63][O:62][CH2:61][CH2:60]4)=[O:33])[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:13]=2[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1)N1CCOCC1
Reaction time: 0.25 h
Yield: 35.2 %

Procedure:
To a solution of 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetic acid (0.05 g, 0.1 mmol, obtained in example 44) in DMF (1 mL), N,N′-dicyclohexylcarbodiimide (0.02 g, 0.1 mmol) and 1-hydroxybenzotriazole (0.02 g, 0.1 mmol) were added under argon atmosphere. The mixture was stirred for 15 min and morpholine (0.01 g, 0.1 mmol) was added. This was stirred at room temperature for 2 days. EtOAc was added and the mixture was filtered. The filtrate was washed with saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using EtOAc-MeOH mixtures of increasing polarity as eluent, to afford 18 mg of title compound (yield: 35%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][C:6]1=2.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:24]1([S:30]([NH:1][CH2:2][CH2:3][S:4][CH:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][O:8][C:7]3[CH:16]=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][C:6]2=3)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)C(SCCN)c1ccccc1CO2
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)C(SCCNS(=O)(=O)c1ccccc1)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 100 ml of pyridine was dissolved 9.00 g of methyl 11-(2-aminoethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound f) obtained in Reference Example 6. Under ice cooling, 4.2 ml of benzenesulfonyl chloride was dropwise added to the solution and the mixture was stirred at room temperature overnight. Pieces of ice were added to the mixture. After stirring for further an hour, the solvent was distilled off under reduced pressure. The residue was extracted with 500 ml of ethyl acetate and the extract was washed in sequence with saturated sodium bicarbonate aqueous solution and then with saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate=7:3) to give 9.90 g of the desired compound.
Reaction SMILES: N[C@H](C=O)CCSC.[CH2:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH:20]([C:26]([O:28]CC)=O)[C:21]([O:23]CC)=O)[CH2:14][CH2:13]1)[CH2:10][CH3:11].Cl.[F:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[F:42])[C:36]([NH2:38])=[NH:37]>CO.Cl>[OH:23][C:21]1[C:20]([CH2:19][CH2:18][C@H:15]2[CH2:14][CH2:13][C@H:12]([CH2:9][CH2:10][CH3:11])[CH2:17][CH2:16]2)=[C:26]([OH:28])[N:37]=[C:36]([C:35]2[CH:39]=[CH:40][C:41]([F:42])=[C:33]([F:32])[CH:34]=2)[N:38]=1
Reactant: CCC[C@H]1CC[C@H](CCC(C(=O)OCC)C(=O)OCC)CC1
Reactant: N=C(N)c1ccc(F)c(F)c1
Agent: CSCC[C@H](N)C=O
Agent: Cl
Solvent: CO
Product: CCC[C@H]1CC[C@H](CCc2c(O)nc(-c3ccc(F)c(F)c3)nc2O)CC1
Yield: 94.2 %

Procedure:
Metal sodium (0.3 g) was dissolved in anhydrous methanol (100 m(), followed by adding diethyl 2-(trans-4'-propylcyclohexyl)ethylmalonate (3.2 g) and 3,4-difluorobenzamidine hydrochloride (1.9 g) with stirring, reacting the mixture under reflux for 10 hours, thereafter cooling the reaction solution, pouring it in 6N HCl (100 ml) and ice (300 g), filtering off deposited yellow crystals, washing with water and drying crystals to obtain 4,6-dihydroxy-5-[2'-(trans-4"-propylcyclohexyl)ethyl]-2-(3,4-difluorophenyl)pyrimidine (3.5 g).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[CH:19]=[CH:18][S:17][C:16]=1[CH:20]=[O:21]>CS(C)=O>[N:5]1[CH:6]=[CH:7][C:2]([S:1][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[CH:20]=[O:21])=[CH:3][CH:4]=1
Reactant: O=Cc1sccc1Cl
Reactant: Sc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1sccc1Sc1ccncc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.2 %

Procedure:
A mixture of 4-mercaptopyridine (1.0 g), potassium carbonate (3.7 g) and dimethyl sulfoxide (10 mL) at 0° C. was treated with 3-chlorothiophene-2-carbaldehyde (1.3 g), and the resulting mixture was stirred at room temperature for 20 hours. The mixture was partitioned between ethyl acetate and water, and the organic phase was washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and petroleum ether (1:9 to 3:2 by volume) to afford the title compound as yellow oil (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13](Cl)=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:16][NH:17][CH3:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13]([N:17]([CH3:18])[CH3:16])=[O:14])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(Cl)N1CC(Sc2ccc(Cl)cc2)C1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)N1CC(Sc2ccc(Cl)cc2)C1
Reaction time: 3 h
Yield: 73.9 %

Procedure:
A solution of 2.6 g (0.01 mole) of 3-[(4-chlorophenyl)thio]-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was stirred while cooling in a water bath and treated with 2.5 ml (0.02 mole) of 40% dimethylamine in water. After stirring for 3 hr, the reaction mixture was diluted with 200 ml of water and the resulting product collected by filtration (2.6 g). Recrystallization from acetone/isopropyl ether yielded 2 g (74.1%) of fine white crystals, m.p. 96°-97° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:29])[CH2:9]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34]C(O)=O.[BH3-]C#N.[Na+]>CO.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]4[CH2:28][CH2:27][N:26]([CH3:34])[CH2:25][CH2:24]4)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:29])[CH2:9]2)=[C:4]([C:30]([F:33])([F:31])[F:32])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C2CCNCC2)c1
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a solution of (2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(3-piperidin-4-ylphenyl)sulfonyl]piperazine (81 mg, 0.155 mmol) in MeOH (2 mL) was added (CHO)n 27 mg, 0.93 mmol), HOAc (13.7 μL, 0.23 mmol) and NaBH3CN (6 mg, 0.093 mmol). The reaction mixture was stirred at room temperature overnight then 50° C. till disappearance of starting material. The reaction was diluted with DCM and quenched with aq. NaHCO3. The organic layer was separated and dried over Na2SO4 and purified on SiO2 gel column eluted with hexanes/EtOAc to give the desired product as a sticky oil (65 mg, 84%). It was redissolved in Et2O and acidified with 1N HCl in Et2O and triturated with hexanes/Et2O to give the titled compound as a white solid. HRMS: calcd for C24H29F4N3O2S+H+, 500.19893. found (ESI-FTMS, [M+H]1+), 500.19765.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[C:4]([NH2:18])[S:3]1.[CH3:19]N>CO.O>[CH3:1][CH:2]1[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)=[C:4]([NH:18][CH3:19])[S:3]1
Reactant: CN
Reactant: CC1SC(N)=C(c2cccc(C(F)(F)F)c2)C1=O
Solvent: CO
Solvent: O
Product: CNC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(C)S1

Procedure:
In this example a mixture containing 5.46 g of 2-methyl-3-oxo-4-(3-trifluoromethylphenyl)-5-amino-2,3-dihydrothiophene; 6.2 g of methyl amine; 9.30 g of water in 20 ml of methanol was placed in a sealed pressure vessel (steel bomb) and heated for 18 hours at 105° C.; then 18 hours at 120° C.; and then 18 hours at 115° C. The mixture was diluted with water and extracted three times with dichloroethane. The extracts were combined and then washed with water, dried over magnesium sulfate and then evaporated affording the title compound as an impure oil residue which was then purified by chromatography over silica gel eluting with methanol:chloroform.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH3:13])[CH:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20][C:21]1[C:25](B(O)O)=[C:24]([CH3:29])[O:23][N:22]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:20][C:21]1[C:25]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[N:6]([CH3:13])[CH:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:24]([CH3:29])[O:23][N:22]=1
Reactant: CN1C(=O)Nc2ccc(Br)cc2C1c1ccccc1
Reactant: Cc1noc(C)c1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)N(C)C(=O)N2

Procedure:
A solution of 6-Bromo-3-methyl-4-phenyl-3,4-dihydro-1H-quinazolin-2-one (15 g, 50.44 mmol) in dioxane (200 mL) is added NaCO3 (5.03 g, 474 mmol) and 3,5-dimethylisoxazole-4-boronic acid (7.8 g, 55.498 mmol) and Pd(dppf)Cl2 (4.268 g, 5.044 mmol) then the mixture is refluxed at 100° C. overnight in dioxane (200 mL). The reaction is concentrated and was purified by chromatography on silica gel to give product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:14](N1C2C=CC=CC=2CN2C(C)=CC=C2C1)=[O:15].[Cl:31]C1C=C(N2C=CC(C)=N2)C=CC=1C(O)=O.C(Cl)(=O)C(Cl)=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:14]([Cl:31])=[O:15]
Reactant: Cc1ccn(-c2ccc(C(=O)O)c(Cl)c2)n1
Reactant: Cc1ccn(-c2ccc(C(=O)N3Cc4ccc(C)n4Cc4ccccc43)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccn(-c2ccc(C(=O)Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Step e) [2-Chloro-4-(3-methylpyrazol-1-yl)-phenyl]-(3-methyl-5H,11H-pyrrolo[2,1-c][1,4]-benzodiazepin-10-yl)-methanone: A mixture of 2-chloro-4-(3-methylpyrazol-1-yl)-benzoic acid (0.18 g) from step c) of Example 10, oxalyl chloride (0.18 g) and one drop of dimethylformamide in dichloromethane (10 ml), was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo, and the residue was redissolved in dichloromethane and reconcentrated in vacuo to yield 2-chloro-4-(3-methyl-pyrazol-1-yl)-benzoyl chloride. A slurry of the acid chloride in dichloromethane (25 ml) was added dropwise to a solution of 10,11-dihydro-3-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.12 g) and diisopropylethylamine (0.10 g) in dichloromethane (25 ml). The mixture was stirred at room temperature for 18 h, and washed with water and saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The solution was concentrated in vacuo and triturated with diethyl ether to yield 0.115 g of product as colorless crystals, m.p. 178-180° C., MS m/z: 417.3 (M+H)+, 833.3 (2M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]([OH:23])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([S:31]([NH:34][CH:35]2[CH2:37][CH2:36]2)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[CH:35]1([NH:34][S:31]([C:27]2[CH:26]=[C:25]([NH:24][C:21]([C:20]3[CH:19]=[N:18][N:11]4[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)=[N:9][C:10]=34)=[O:23])[CH:30]=[CH:29][CH:28]=2)(=[O:33])=[O:32])[CH2:37][CH2:36]1
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NC2CC2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Yellow solid. MS (ISP) 534.1 [(M−H)−]; mp 257° C.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[O:20][C:21]([C:24](Cl)=[O:25])=[CH:22][CH:23]=2)=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[O:20][C:21]([C:24](=[O:25])[NH:2][CH3:1])=[CH:22][CH:23]=2)=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.97 ml (5.94 mmol) of a 2 M solution of methylamine in THF were initially charged in 20 ml of THF, and a solution of 0.8 g (2.4 mmol) of 1-benzyl-3-(5-chlorocarbonyl-2-furyl)indazole in 10 ml of THF was added dropwise at RT. After 1 h, the mixture was poured into ice-water and the oil that separated off was extracted with ethyl acetate. The organic phase was washed with 1 N hydrochloric acid, dried and concentrated using a rotary evaporator. The crude product was recrystallized from isopropanol. This gave 0.44 g (55%) of the title compound. m.p.: 182-183° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[C:6](Cl)[N:5]=1.[C:15]([O:19][C@@H:20]([C@H:22]1[CH2:26][O:25][C:24](=[O:27])[NH:23]1)[CH3:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C@@H:20]([C@H:22]1[CH2:26][O:25][C:24](=[O:27])[N:23]1[C:6]1[N:5]=[C:4]([Cl:3])[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=1)[CH3:21])([CH3:16])([CH3:17])[CH3:18]
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 23 mg, 0.58 mmol, 1.2 equiv) was added to a solution of methyl 2,6-dichloropyrimidine-4-carboxylate (100 mg, 0.483 mmol) and (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (90 mg, 0.483 mmol, 1 equiv) in DMF (2.4 mL) at 0° C. The suspension was stirred at 0° C. for 1 hour, by which time it turned yellow. The reaction was quenched with dilute aqueous sodium chloride (20 mL) and extracted with ethyl acetate (2×20 mL). The combined extracts were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) separated the regioisomers and provided methyl 6-((R)-4-((R)-1-(tert-butoxy)ethyl)-2-oxooxazolidin-3-yl)-2-chloropyrimidine-4-carboxylate (0.111 g, white solid) in 64% yield. 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 4.76 (m, 1H), 4.69 (dd, J=9.4, 2.7 Hz, 1H), 4.52-4.41 (m, 2H), 4.02 (s, 3H), 1.26 (s, 9H), 1.05 (d, J=6.6 Hz, 3H). MS m/z 358.2 (M+H)+; Rt-1.00 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH2:8][CH2:9][CH2:10][N:11](CCN)CCN.O.[N+]([O-])([O-])=O.[Ga+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[N:8][CH2:9][CH2:10][NH2:11]
Reactant: O=Cc1ccc[nH]1
Reactant: NCCN(CCN)CCN
Agent: O=[N+]([O-])[O-]
Agent: [Ga+3]
Solvent: O
Product: NCCN=Cc1ccc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The ligand [(((pyrrole-2-yl)methylidene)amino)ethyl]amine was prepared by adding a methanolic solution of pyrrole-2-carboxaldehyde (1.430 g, 15 mmol, 100 mL) to a methanolic solution of tris(2-aminoethyl)amine (0.720 g, 5 mmol, 10 mL). The resulting yellow solution was stirred at room temperature for 30 min. A methanolic solution of gallium(III) nitrate hydrate (1.280 g, 5 mmol, 150 mL) was added to the ligand solution and stirred at room temperature for 30 min. The solution was filtered and left to stand at ambient temperature until crystallization occurred. The crude material was then sublimed at 235° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=4[Cl:31])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C>[N:32]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[Cl:31])[CH:17]=[C:18]([F:23])[CH:19]=2)[O:14]1)=[N+:33]=[N-:34]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cc(F)cc(-c4cc(Cl)ccc4Cl)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1CCc2cc(F)cc(-c3cc(Cl)ccc3Cl)c2O1
Reaction time: 0.17 h
Yield: 80.2 %

Procedure:
A solution ((R)-8-(2,5-dichlorophenyl)-6-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (410 mg, 0.85 mmol) and sodium azide (280 mg, 4.3 mmol) in anhydrous DMF (20 mL) was heated to 90° C. under nitrogen for 20 hours. The cooled reaction mixture was quenched by the addition of water (30 mL) and the resulting suspension stirred vigorously for 10 minutes. The mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase separated, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Chromatography with 0–30% ethyl acetate in hexanes afforded 240 mg (83%) of (2R)-2-azidomethyl-8-(2,5-dichloro-phenyl)-6-fluoro-chroman as a colorless oil. MS (APPI) m/z 322 ([M−N2+H]+).
Reaction SMILES: [CH:1]1([C:4]2([F:25])[CH2:7][N:6]([C:8]3[N:13]=[C:12]([S:14]([CH3:17])(=O)=O)[N:11]=[C:10]([NH:18][C:19]4[NH:23][N:22]=[C:21]([CH3:24])[CH:20]=4)[CH:9]=3)[CH2:5]2)[CH2:3][CH2:2]1.[NH2:26][C:27]1[N:32]=[CH:31]C(S)=[CH:29][CH:28]=1>CN(C=O)C.C(OC(=O)C)C.C([O-])(O)=O.[Na+]>[NH2:26][C:27]1[N:32]=[CH:31][C:17]([S:14][C:12]2[N:11]=[C:10]([NH:18][C:19]3[NH:23][N:22]=[C:21]([CH3:24])[CH:20]=3)[CH:9]=[C:8]([N:6]3[CH2:7][C:4]([CH:1]4[CH2:3][CH2:2]4)([F:25])[CH2:5]3)[N:13]=2)=[CH:29][CH:28]=1
Reactant: Cc1cc(Nc2cc(N3CC(F)(C4CC4)C3)nc(S(C)(=O)=O)n2)[nH]n1
Reactant: Nc1ccc(S)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(N3CC(F)(C4CC4)C3)nc(Sc3ccc(N)nc3)n2)[nH]n1
Reaction time: 2 h
Yield: 30 %

Procedure:
A solution of 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (880 mg, 2.4 mmol) and 6-aminopyridine-3-thiol) (300 mg, 2.4 mmol) in DMF (10 ml) was heated to 80° C. and stirred for 2 hrs. The reaction was diluted with ethylacetate (150 ml) and Sat. NaHCO3 (50 ml) and the organic layer washed with brine (50 ml), dried (MgSO4) and concentrated to give an oil. The residue was purified by flash column chromatography eluting with Pentane/EtOAc (5% MeOH) 0 to 100%. The resulting compound was triturated in 10:1 DCM:MeOH and filtered to give the title compound as a white solid (300 mg, 30%). 1H NMR (DMSO, 400 MHz) 0.42-0.44 (2H, m), 0.55-0.60 (2H, m), 1.35-1.45 (1H, m), 2.11 (3H, s), 3.81-3.90 (4H, m), 5.55-5.80 (2H, m), 6.35 (2H, s), 6.49-6.52 (1H, d), 7.46-7.49 (1H, d), 7.97 (1H, s), 9.30-9.35 (1H, s). ES+ 413