Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C[O-].[Na+].CI.[OH-].[Na+]>CO>[CH2:7]([S:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Sc1ccc(Br)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CI
Product: CCCCSc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Bromobenzenethiol (5 g, 26.44 mmol) was added to a solution of sodium methoxide (1.43 g, 26.48 mmol) in 20 ml of anhydrous methanol. The mixture was stirred for 30 min under nitrogen at room temperature and a solution of methyl iodide (4.51 g, 31.77 mmol) in 20 ml anhydrous methanol was then added. The reaction mixture was stirred overnight at room temperature, poured into 2 M of NaOH aqueous solution (30 ml) and extracted three times with ether (3×100 ml ). The combined organic layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of solvent, the product was purified by distillation at 117-119° C. (0.5 mmHg) and was isolated in 88.4% (5.72 g) yield.
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]([CH:17]([CH3:19])[CH3:18])[C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([SH:14])[S:13][C:9]=2[CH:8]=1)=[O:5])#[N:2].[CH:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)=O.N1CCCCC1>C(O)C>[C:1]([C:3]([C:4](=[O:5])[N:6]([CH:17]([CH3:19])[CH3:18])[C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([SH:14])[S:13][C:9]=2[CH:8]=1)=[CH:20][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)#[N:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(C)N(C(=O)CC#N)c1ccc2nc(S)sc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)N(C(=O)C(C#N)=Cc1ccc(C(=O)O)cc1)c1ccc2nc(S)sc2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
α-cyano-N-isopropyl-N-(2-mercaptobenzothiazol-6-yl)acetamide (99 mg, 0.339 mmol) and 4-formylbenzoic acid (56 mg, 0.374 mmol) were combined in absolute ethanol (1.4 ml). The mixture was stirred 15 minutes with activated 4A molecular sieves in a sealed vessel. Piperidine (67 μL, 0.678 mmol) was added and the mixture was heated to 80° C. After 1 hour, the solution was concentrated in vacuo and purified by preparative TLC (10% methanol, 90% dichloromethane) to yield 49 mg (34%). 1H NMR(CDCl3) δ1.17 (d, 6H), 4.93 (m, 1H), 7.16 (dd, 1H), 7.28 (dd, 1H), 7.32 (d, 1H), 7.69 (d, 2H), 7.93 (s, 1H), 7.98 (d, 2H); ESIMS: m/z 422 (M−H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[N:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([Cl:10])=[CH:9][N:4]2[N:3]=1.NC1C(C(ON2C3C=CC=CC=3N=N2)=O)=C2N=C[C:35]([CH2:37][C:38]#[N:39])=CN2N=1.C([O-])=O.[NH4+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[N:21]2[CH2:26][CH2:25][CH:24]([N:39]3[CH2:35][CH2:37][CH2:38]3)[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([Cl:10])=[CH:9][N:4]2[N:3]=1
Reactant: Nc1nn2cc(Cl)cnc2c1C(=O)Nc1cnccc1N1CCC(=O)CC1
Reactant: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Nc1nn2cc(Cl)cnc2c1C(=O)Nc1cnccc1N1CCC(N2CCC2)CC1
Temperature: 25 °C

Procedure:
A solution of 2-amino-6-chloro-N-[4-(4-oxo-1-piperidyl)-3-pyridyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (50 mg, 0.1296 mmol), azetidine (Hydrochloric Acid (1)) (12.12 mg, 0.1296 mmol) and ammonium formate (8.172 mg, 0.1296 mmol) in toluene was heated at reflux for 1 h with a Dean-Stark apparatus. The reaction was cooled to room temperature and evaporated. The resulting yellow solid was dissolved in DMSO and purified by fractionlynx to yield 2-amino-N-(4-(4-(azetidin-1-yl)piperidin-1-yl)pyridin-3-yl)-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. (27 mg, 31%). MS (ES+) 427.2.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]([CH:27]([C:54]([F:59])([F:58])[CH2:55][CH2:56][CH3:57])[CH2:28][CH2:29][CH2:30][C@H:31]1[C@H:35]([OH:36])[CH2:34][C@H:33]([O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)[C@@H:32]1[CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][C:50]([O:52][CH3:53])=[O:51])[Si](C(C)(C)C)(C)C>C1COCC1>[OH:19][CH:27]([C:54]([F:59])([F:58])[CH2:55][CH2:56][CH3:57])[CH2:28][CH2:29][CH2:30][C@H:31]1[C@H:35]([OH:36])[CH2:34][C@H:33]([O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)[C@@H:32]1[CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][C:50]([O:52][CH3:53])=[O:51]
Reactant: CCCC(F)(F)C(CCC[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](OC2CCCCO2)C[C@H]1O)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCC(F)(F)C(O)CCC[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](OC2CCCCO2)C[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Tetrabutylammonium fluoride (1.0M in THF, 3.95 ml) was added to a solution of the monoalcohol (40) (0.479 g) in THF and the mixture was stirred overnight at room temperature. The crude product obtained after the usual work-up was subjected to silicagel column chromatography to give the diol (41).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.O.[F:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1B(O)O>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[F:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Reactant: OB(O)c1ccncc1F
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: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3F)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 20.1 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.12 g) and 3-fluoropyridine-4-boronic acid hydrate (0.061 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.050 g) to obtain the title compound (0.025 g) as a yellowish foam. MS (ISP): 485.3 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH:22]2[C:28]([O:30]C)=[O:29])[O:10][C:9]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH:22]2[C:28]([OH:30])=[O:29])[O:10][C:9]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CC(=O)CCC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(Cc2ccccc2)C(CC2CCC(=O)CC2C(=O)O)OC1(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.6 %

Procedure:
A solution of 4-benzyl-5-(2-methoxycarbonyl-4-oxo-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.81 g, 3.94 mmol) in dry tetrahydrofuran (24 ml) was treated with 1M aqueous lithium hydroxide solution (8 ml 7.88 mM). The resulting mixture was stirred at room temperature for 6 hours then diluted with ethyl acetate, washed with a 1:1 mixture of brine and 1 M hydrochloric acid, dried (anhydrous magnesium sulfate) and concentrated in vacuo to give 4-benzyl-5-(2-carboxy-4-oxo-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.66 g, 95%) as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[NH:12][C:11]=2[CH:21]=1)([O:3][CH2:4][CH3:5])=[O:2].[Br:22][CH:23]([CH3:27])[C:24](Cl)=[O:25].Cl>C1(C)C=CC=CC=1>[C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]([C:24](=[O:25])[CH:23]([Br:22])[CH3:27])[C:11]=2[CH:21]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)Nc1ccc2c(c1)Nc1ccccc1CC2
Reactant: CC(Br)C(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1ccc2c(c1)N(C(=O)C(C)Br)c1ccccc1CC2
Temperature: 25 °C
Yield: 93.5 %

Procedure:
The starting material can be synthesized as follows. 3-Carbethoxyamino-10,11-dihydro-5H-dibenz[b,f]azepine (28.2 g, 0.1 moles) is mixed with 300 ml toluene and 20 g (0.11 moles) of 2-bromopropionyl chloride and stirred for 4 hours on a boiling water bath, while HCl gas is escaping. The mixture is allowed to cool to room temperature and filtered and the filtrate is evaporated to dryness under reduced pressure. Upon addition of diethyl ether, the residue crystallizes, after temporarily going into solution. The crystalline deposit is filtered off with suction, washed with ether and dried. 3-Carbethoxyamino-5-(α-bromopropionyl)-10,11-dihydro-5H-dibenz[b,f]azepine (39 g) is obtained, which is purified by recrystallization from the 5-fold amount of isopropanol.
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1.C(OCC)(=O)C>CN(C=O)C>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:6]2[C:2]([CH3:1])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:3](=[O:20])[N:4]([C:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][CH:11]=3)=[O:9])[C:5]2=[O:7])=[CH:32][CH:31]=1
Reactant: CC1(c2ccccc2)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(c2ccccc2)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
5-Methyl-3-naphthylcarbonyl-5-phenylimidazolidine -2,4-dione (43 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 4-fluorobenzyl bromide (24 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 38 mg of white crystals.
Reaction SMILES: [I-:1].[K+].N[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[S:15])[N:13]([CH3:16])[N:12]=[C:11]2[C:17]([F:20])([F:19])[F:18])=[C:6]([Cl:21])[CH:5]=1.N([O-])=O.[Na+].S(=O)(=O)(O)O>O>[Cl:21][C:6]1[CH:5]=[C:4]([I:1])[CH:9]=[CH:8][C:7]=1[N:10]1[C:14](=[S:15])[N:13]([CH3:16])[N:12]=[C:11]1[C:17]([F:20])([F:19])[F:18]
Reactant: [I-]
Reactant: Cn1nc(C(F)(F)F)n(-c2ccc(N)cc2Cl)c1=S
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Cn1nc(C(F)(F)F)n(-c2ccc(I)cc2Cl)c1=S
Temperature: 0 °C
Yield: 36.8 %

Procedure:
To a stirred, warm (40° C.) solution of 10.8 g (0.0648 mole) of potassium iodide in 80 ml of water was added dropwise a solution of 10.0 g (0.0324 mole) of 4-(4-amino-2-chlorophenyl)-3-trifluoromethyl-4,5-dihydro-1-methyl-1,2,4-triazol-5(1H)-thione (Compound 94 of Table 1, prepared in Step C of Example 2), 2.70 g (0.389 mole) of sodium nitrite, and 20.0 g (0.204 mole) of concentrated sulfuric acid in 125 g of ice-cold water. The resultant mixture was stirred at 40° C. for three hours. The mixture was cooled and was extracted with methylene chloride. The extract was washed with an aqueous sodium metabisulfite solution. The washed organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure, leaving a residue. This residue was purified by column chromatography on silica gel, eluting with petroleum ether:diethyl ether (75:25) to yield 5.0 g of 4-(2-chloro-4-iodophenyl)-3-trifluoromethyl-4,5-dihydro-1-methyl-1,2,4-triazol-5(1H)-thione as a solid, mp 117°-119° C., Compound 91 of Table 1. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[C:6]([CH2:7]O)=[CH:5][N:4]([C:9]([CH2:12][CH3:13])([CH3:11])[CH3:10])[N:3]=1.C(N(CC)CC)C.CS([Cl:25])(=O)=O>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[C:6]([CH2:7][Cl:25])=[CH:5][N:4]([C:9]([CH2:12][CH3:13])([CH3:11])[CH3:10])[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C)(C)n1cc(CO)c(Br)n1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)(C)n1cc(CCl)c(Br)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A solution of (3-bromo-1-tert-pentyl-1H-pyrazol-4-yl)methanol (675 mg, 2.73 mmol) in dichloromethane (10 mL) was cooled to 0° C. Triethylamine (0.53 mL, 3.8 mmol) and methanesulfonyl chloride (0.28 mL, 3.6 mmol) were added. The reaction was stirred at 0° C. for 15 minutes, then warmed to room temperature and stirred for 1.5 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give the title compound (725 mg, 100%) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 7.48 (s, 1H), 4.47 (s, 2H), 1.86 (q, J=7.48 Hz, 2H), 1.52 (s, 6H), 0.69 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:13])([CH3:12])[C:5](=[O:11])[NH:6]2.C(O)(=O)C.[Br:18]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:18][C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5](=[O:11])[C:4]2([CH3:13])[CH3:12]
Reactant: CC1(C)C(=O)Nc2cccc(F)c21
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1(C)C(=O)Nc2ccc(Br)c(F)c21
Reaction time: 24 h
Yield: 64.6 %

Procedure:
4-Fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1 g, 22.9 mmol) was dissolved in dichloromethane (DCM) (50 mL) and acetic acid (2 mL) at room temperature. Bromine (0.386 mL, 7.5 mmol) was added and the solution allowed to stir 24 hours. The reaction mixture was poured into sodium thiosulfate solution, extracted with diethyl ether, the combined organic layers were dried over magnesium sulfate and evaporated. Trituration of the crude product with hexane gave 5-bromo-4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.25 g, 87%): HRMS [M−H]− 255.9781
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][N:25]([CH2:27][C@@H:28]([OH:30])[CH3:29])[CH2:24]4)[C:15]=3[O:31][CH3:32])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.NC1N=CN=C2N([C@H](C3C=C(Cl)C(C#N)=C(C4CN(C[C@H](O)C)C4)C=3OC)C)N=C(C)C=12.NC1N=CN=C2N([C@@H](C3C=C(Cl)C(C#N)=C(C4CN(C[C@H](O)C)C4)C=3OC)C)N=C(C)C=12>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][N:25]([CH2:27][CH:28]([OH:30])[CH3:29])[CH2:24]4)[C:15]=3[O:31][CH3:32])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: COc1c([C@@H](C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C[C@H](C)O)C1
Agent: COc1c([C@@H](C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C[C@@H](C)O)C1
Agent: COc1c([C@H](C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C[C@@H](C)O)C1
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(CC(C)O)C1

Procedure:
Based on the stereochemistry of Example 269, the stereochemistry of each diastereomer is believed to be 4-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-((S)-2-hydroxypropyl)azetidin-3-yl)-3-methoxybenzonitrile (Example 361), 4-((5)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-((R)-2-hydroxypropyl)azetidin-3-yl)-3-methoxybenzonitrile (Example 362), and 4-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-((R)-2-hydroxypropyl)azetidin-3-yl)-3-methoxybenzonitrile (Example 363) (structures shown below)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[O:22].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH:21]([C:20]1[CH:19]=[C:18]([CH:25]=[CH:24][CH:23]=1)[O:17][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11])=[O:22]
Reactant: O=Cc1cccc(O)c1
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(C=O)c1
Yield: 87.4 %

Procedure:
A solution of (E)-methyl 2-(2-(bromomethyl)phenyl)-3-methoxyacrylate (3.0 g, 10.52 mmol), 3-hydroxybenzaldehyde (1.41 g, 1.1 eq) and potassium carbonate (3.0 g, 3.0 eq) in a mixture of acetonitrile (CH3CN, 30 mL)/H2O (5 mL) was refluxed for 15 hours. After concentration in a vacuum to remove the reaction solvent, the residue was stirred in water (50 mL) and the aqueous layer was extracted twice with 50 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum to remove the solvent. Purification by silica gel chromatography afforded (E)-methyl 2-(2((3-formylphenoxy)methyl)phenyl)-3-methoxyacrylate as a white solid (3.0 g, yield 87%).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11]([C:21](=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH:21]([OH:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CC(OCc2ccccc2)C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)CC(O)C1(NC(=O)OC(C)(C)C)CC(OCc2ccccc2)C1
Yield: 91.2 %

Procedure:
A 38.84 g (99.22 mmol) portion of ethyl 3-[1-benzyloxy-3-(tert-butoxycarbonylamino)cyclobutan-3-yl]-3-oxopropionate was dissolved in 300 ml of methanol to which, while cooling in an ice bath with stirring, was subsequently added 1.617 g (42.75 mmol) of sodium tetrahydroborate in five portions. After 10 minutes of stirring at the same temperature, to this was gradually added saturated ammonium chloride aqueous solution. After evaporation of methanol under a reduced pressure, ethyl acetate was added to the thus obtained residue to effect separation of layers. The resulting organic layer was washed with saturated brine, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure and the resulting residue was purified by a silica gel column chromatography to give 35.61 g (91.2%) of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[CH:6][C:5]=1[OH:24].[I-].[Na+].Cl[CH:28]([S:32][CH3:33])[C:29]([NH2:31])=[O:30]>O.C(COC)OC>[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[CH:6][C:5]=1[O:24][CH:28]([S:32][CH3:33])[C:29]([NH2:31])=[O:30]
Reactant: CSC(Cl)C(N)=O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSC(Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(N)=O
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a mixture of 1.3 g of sodium hydride and 100 ml of dimethoxyethane, 10 g of 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenol were added at room temperature and stirred for 30 minutes. Then, 2.2 g of sodium iodide and 6.7 g of crude 2-chloro-2-(methylthio)acetamide were added thereto and stirred at room temperature for 3 hours, and water was poured into the reaction mixture. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate) to give 10.2 g of 2-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-2-(methylthio)acetamide.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[CH:19][N:20]=[CH:21][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+].Cl>ClCCl>[O:15]1[CH2:16][CH2:17][N:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)(=[O:10])=[O:11])[C:13]2[CH:21]=[N:20][CH:19]=[CH:18][C:14]1=2
Reactant: COc1ccc(S(=O)(=O)N2CCOc3ccncc32)cc1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: O=S(=O)(c1ccc(O)cc1)N1CCOc2ccncc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.2 %

Procedure:
In a 100 ml flask, 4-(4-methoxy-benzenesulfonyl)-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (699 mg, 2.282 mmol) was dissolved in dichloromethane (30 ml) and the mixture was cooled to 0□. 1.0M Boron tribromide dissolved in dichloromethane (11.4 ml, 11.4 mmol) was added thereto and stirred at room temperature for 16 hours. After neutralizing with saturated solution of sodium hydrogen carbonate to pH 8 to 9, the mixture was adjusted to pH 6 again by using 1N hydrochloric acid and extracted with dichloromethane. The combined organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of methanol:dichloromethane=1:20. The fractions containing the product were collected and evaporated to obtain white solid (375 mg, 56.2%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:19]2[C:23]([CH2:24][N:25]3C(=O)C4=CC=CC=C4C3=O)=[N:22][N:21]=[C:20]2[Br:36])=[C:8]([CH:18]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=O)([O-:3])=[O:2].NN>>[Br:36][C:20]1[N:19]2[C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][C:8]=3[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:25][CH2:24][C:23]2=[N:22][N:21]=1
Reactant: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-n1c(Br)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(Br)n1-2

Procedure:
The 5-nitro-2-(3-bromo-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl)-2'-chlorobenzophenone is reacted with hydrazine to form the titled compound.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[Br:27][C:28]1[C:29]([NH2:35])=[N:30][CH:31]=[N:32][C:33]=1Cl.[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[NH2:35][C:29]1[N:30]=[CH:31][N:32]=[C:33]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:8](=[O:16])[C:7]3=[C:17]([S:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[C:28]=1[Br:27]
Reactant: Nc1ncnc(Cl)c1Br
Reactant: C[C@H](N)c1nn2ccc(Sc3ccccc3)c2c(=O)n1-c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1Br)c1nn2ccc(Sc3ccccc3)c2c(=O)n1-c1ccccc1
Yield: 110.3 %

Procedure:
(S)-2-(1-Aminoethyl)-3-phenyl-5-(phenylthio)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (142 mg, 0.39 mmol) was treated with treated 5-bromo-6-chloropyrimidin-4-amine (245 mg, 1.18 mmol), cesium fluoride (178 mg, 1.17 mmol), N,N-diisopropylethylamine (341 μl, 1.96 mol) according to Preparation 13 to give 0.23 g (75% yield) of the title compound as a solid.