Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][S:5](=[O:9])(=[O:8])[NH:4]1)[CH3:2].[CH3:10][C:11]1[C:12]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=3)=[O:25])[CH2:20][CH2:19]2)=[N:13][CH:14]=[C:15]([CH3:17])[CH:16]=1>>[CH3:10][C:11]1[C:12]([N:18]2[CH2:19][CH2:20][N:21]([C:24]([C:26]3[CH:31]=[CH:30][C:29]([N:4]4[C@H:3]([CH2:1][CH3:2])[CH2:7][CH2:6][S:5]4(=[O:9])=[O:8])=[CH:28][CH:27]=3)=[O:25])[CH2:22][CH2:23]2)=[N:13][CH:14]=[C:15]([CH3:17])[CH:16]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CC[C@@H]1CCS(=O)(=O)N1
Product: CC[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Yield: 12.9 %

Procedure:
Using (R)-3-ethylisothiazolidine 1,1-dioxide (150 mg) described in Preparation Example 3 and [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (421 mg) described in Preparation Example 113 and by the reaction and treatment in the same manner as in Example 1, the title compound (57 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH2:23]([O+](CC)CC)[CH3:24]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C:13]([O:17][CH2:23][CH3:24])=[N:14][CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC1=NCCN(C(=O)OCc2ccccc2)C1
Reaction time: 72 h
Yield: 94.2 %

Procedure:
To a solution of 3-oxo-piperazine-1-carboxylic acid benzyl ester (2.0 g, 8.54 mmol, Maybridge) in dichloromethane (18 mL) at room temperature was added triethyloxonium tetrafluoroborate (4.1 g, 21.3 mmol). This mixture was allowed to stir for about 3 days then quenched by the addition of ice chips followed by saturated aqueous sodium bicarbonate until a neutral pH was obtained. The organic layer was separated and the aqueous layer was extracted with chloroform (3×). The combined organic extracts were washed with brine (1×), dried over sodium sulfate, and concentrated to give 2.11 g (95%) of the title compound of Example 259, Step A as a slightly yellow oil that was sufficiently pure to carry on to the next step. 1H NMR (CDCl3, 300 MHz) δ 7.43-6.97 (c, 5H), 5.17 (s, 2H), 4.10 (q, 2H), 3.98 (s, 2H), 3.60-3.40 (c, 4H), 1.27 (t, 3H); MS (APCI) 263 (MH+).
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.[O:24]=[C:25]([C:29]1[O:30][CH:31]=[CH:32][CH:33]=1)[C:26](O)=[O:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[O:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:25](=[O:24])[C:26]([N:3]1[CH2:4][CH:5]2[C:1]([C:7]3[CH:8]=[CH:9][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:11][CH:12]=3)([CH2:6]2)[CH2:2]1)=[O:27]
Reactant: O=C(O)C(=O)c1ccco1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(C(=O)C(=O)c3ccco3)C4)cc2)C(=O)O1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
To a stirred solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (163 mg, 0.46 mmol), in DMF (20 mL), were added α-oxo-2-furanacetic acid (65 mg, 0.46 mmol), EDC (97 mg, 0.51 mmol), HOBt (69 mg, 0.51 mmol) and NMM (0.11 mL, 1.02 mmol) at 0° C. The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, DMF was evaporated in vacuo and residue was dissolved in chloroform (50 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.4:9.6 MeOH:CHCl3) to provide the title compound (140 mg, 69%) as white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[N:27]=[C:26]([C:28](OC)=[O:29])[O:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:32]=1.[CH3:33][NH:34][CH3:35].C1COCC1>C1COCC1>[CH3:33][N:34]([CH3:35])[C:28]([C:26]1[O:25][N:24]=[C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:32]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:18]=2)[N:27]=1)=[O:29]
Reactant: CNC
Reactant: COC(=O)c1nc(-c2cccc(N3C[C@@H]4CCCN4c4nc(SC)ncc4C3=O)c2)no1
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(C(=O)N(C)C)n3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
Methyl (S)-3-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazole-5-carboxylate (162 mg, 0.36 mmol) obtained in Step 1 of Example 80 was dissolved in THF (3.0 mL), and the mixture was stirred at room temperature for 2 hours after adding a 2.0 mol/L dimethylamine/THF solution (1.80 mL, 3.58 mmol). The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)—N,N-dimethyl 3-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazole-5-carboxamide (151 mg, 90%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24].[F:31][C:32]([Si](C)(C)C)([F:34])[F:33].Cl>C1COCC1>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]([OH:24])[C:32]([F:34])([F:33])[F:31]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccccc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
Tetrabutylammonium fluoride (0.1 ml; 1.0 M solution in tetrahydrofuran) was added to a solution of 2-trifluoromethyl-benzaldehyde (1.74 g, 10 mmol) and trifluoromethyltrimethylsilane (TMSCF3) (1.8 ml, 12 mmol) in 10 ml THF at 0° C. The formed mixture was warmed up to room temperature and stirred for 4 hours. The reaction mixture was then treated with 12 ml of 1N HCl and stirred overnight. The product was extracted with ethyl acetate (3×20 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 2.2 g of 1-(2-trifluoromethylphenyl)-2,2,2-trifluoro-ethanol, yield 90%.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:3][C:2]2=[O:1])=[CH:13][CH:12]=1
Reactant: COc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of (3R,4R)-tert-butyl 3-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate (180 mg, 0.59 mmol) in DCM (3 mL) at 0° C. under N2 was added Dess-Martin Periodinane (373 mg, 0.88 mmol). The mixture was allowed to warm to rt and stirred for 3 h. The reaction mixture was directly purified via silica gel chromatography eluting with 30% EtOAc in hexanes to afford tert-butyl 4-(4-methoxyphenyl)-3-oxopiperidine-1-carboxylate (155 mg, 87% yield). Subsequent results revealed that the 4R stereochemistry is lost in this reaction and the racemic product was obtained. 1H NMR (500 MHz, chloroform-d) δ 7.09-7.03 (m, 2H), 6.93-6.87 (m, 2H), 4.24 (d, J=18.0 Hz, 1H), 4.11-4.02 (m, 1H), 3.80 (s, 3H), 3.61 (dd, J=11.9, 5.6 Hz, 1H), 3.56-3.46 (m, 1H), 2.34-2.16 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:18].Cl.[OH:25][NH2:26].Cl>N1C=CC=CC=1>[OH:25][N:26]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:18]
Reactant: NO
Reactant: CC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Solvent: c1ccncc1
Product: CC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=NO

Procedure:
A stirred solution of (1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid (5.1 g., 0.015 mole) and hydroxyamine hydrochloride (3.2 g., 0.045 mole) in pyridine (60 ml.) is heated at 95°C. on a steam bath for 40 hours then poured into aqueous hydrochloric acid affording (1-hydroxyimino-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 230°C. after recrystallization from ethanol-water.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[CH3:27][C:28]1[O:29][C:30]2[C:31](=[C:33]([C:37](O)=[O:38])[CH:34]=[CH:35][CH:36]=2)[CH:32]=1.[OH-].[Na+]>O.CO>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:30]3[O:29][C:28]([CH3:27])=[CH:32][C:31]=23)=[O:38])[CH2:7]1
Reactant: Cc1cc2c(C(=O)O)cccc2o1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc3oc(C)cc23)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-methyl-benzofuran-4-carboxylic acid which was synthesised by saponification of the corresponding methyl ester derivative (Ishikawa T. et al. Heterocycles 1994, 39, 1, 371-380) with NaOH in a mixture water/MeOH.
Reaction SMILES: [F:1][C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=3)[CH3:12])[C:6]=2[CH:22]=1>C1COCC1.[Ni]>[NH2:19][C:15]1[CH:14]=[C:13]([CH:11]([N:7]2[C:6]3[CH:22]=[C:2]([F:1])[C:3]([F:23])=[CH:4][C:5]=3[O:9][C:8]2=[O:10])[CH3:12])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(c1cccc([N+](=O)[O-])c1)n1c(=O)oc2cc(F)c(F)cc21
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(c1cccc(N)c1)n1c(=O)oc2cc(F)c(F)cc21
Reaction time: 24 h

Procedure:
633 mg (1.98 mmol) of 5,6-difluoro-3-[1-(3-nitrophenyl)ethyl]-3H-benzoxazol-2-one are dissolved in 10 ml of THF and hydrogenated under a hydrogen atmosphere using 700 mg of Raney nickel (water-wet). After 24 h, the reaction solution is filtered, the filtrate is evaporated to dryness, and the residue is crystallised from diethyl ether/petroleum ether.
Reaction SMILES: [F:1][CH:2]([F:21])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:5]1.[H-].[Na+].[CH3:24][O:25][CH2:26][CH2:27][N:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[N:30]=[C:29]1S(C)(=O)=O.O>CN(C=O)C>[F:21][CH:2]([F:1])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:29]3[N:28]([CH2:27][CH2:26][O:25][CH3:24])[C:32]4=[N:33][CH:34]=[CH:35][CH:36]=[C:31]4[N:30]=3)=[CH:16][CH:15]=2)=[N:5]1
Reactant: COCCn1c(S(C)(=O)=O)nc2cccnc21
Reactant: Oc1ccc(-c2nn(CC(F)F)c3cc(F)cnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1c(Oc2ccc(-c3nn(CC(F)F)c4cc(F)cnc34)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
To a stirred solution of 4-[1-(2,2-difluoroethyl)-6-fluoro-1H-pyrazolo[4,3-b]pyridin-3-yl]phenol (47 mg) in DMF (4 mL) was added NaH (60% in oil, 4.23 mg) at room temperature. The mixture was stirred at room temperature for 30 min, and then 3-(2-methoxyethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (52 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane). The product was crystallized from EtOH/hexane to give the title compound (32.0 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[CH:11][C:10]([C:14](OCC)=[O:15])=[C:9]1[C:19]([O:21]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:25][NH2:26].Cl>COCCOCCOC>[CH2:1]([N:8]1[C:9]2[C:19](=[O:21])[NH:25][NH:26][C:14](=[O:15])[C:10]=2[CH:11]=[C:12]1[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cc(C)n(Cc2ccccc2)c1C(=O)OCC
Agent: Cl
Solvent: O
Solvent: COCCOCCOC
Product: Cc1cc2c(=O)[nH][nH]c(=O)c2n1Cc1ccccc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A solution of 175.3 g (0.56 mol) of diethyl 1-benzyl-5-methylpyrrole-2,3-dicarboxylate and 540 ml (11.1 mol) of hydrazine hydrate in 880 ml of diglyme is heated to 110° C. After 2 h, a further 270 ml (5.5 mol) of hydrazine hydrate are added dropwise in the course of 90 min. The mixture is subsequently stirred at 110° C. for a further 16 h. After cooling and addition of 2 1 of ice-water, the mixture is adjusted to pH 5 with conc. hydrochloric acid. The precipitate is filtered with suction and washed with 5 1 of water. After drying over potassium hydroxide in a high vacuum and precipitating from diisopropyl ether/ethyl acetate, 127.3 g (89%) of the title compound are isolated. M.p.: 322°-324° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([CH:13](O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([CH:13]([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:23][C:24]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: OC(c1ccccc1)c1ccc(OCc2ccccc2)cc1
Product: CCOC(=O)c1[nH]c2ccccc2c1C(c1ccccc1)c1ccc(OCc2ccccc2)cc1
Yield: 94.5 %

Procedure:
Substantially the same procedure as in Reference Example 4 was repeated using 4-benzyloxybenzhydrol (30.0 g, 103 mmol) and ethyl indole-2-carboxylate (18.5 g, 97.9 mmol) to give 42.7 g (yield: 95%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[C:10]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:9]([C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:26])=[CH:7][C:5]=2[N:6]=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[B]1OC2C(=CC=CC=2)O1.BrC1SC2C(OS(C(F)(F)F)(=O)=O)=C([C@H](O)C(OCC)=O)C(C)=CC=2N=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:3][C:4]2[C:10]([O:11][S:12]([C:15]([F:18])([F:16])[F:17])(=[O:14])=[O:13])=[C:9]([C@H:19]([OH:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:26])=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)C(=O)c1c(C)cc2nc(Cl)sc2c1OS(=O)(=O)C(F)(F)F
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: CCOC(=O)[C@@H](O)c1c(C)cc2nc(Br)sc2c1OS(=O)(=O)C(F)(F)F
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](O)c1c(C)cc2nc(Cl)sc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 0.75 h

Procedure:
To a solution of ethyl 2-(2-chloro-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)-2-oxoacetate (0.6621 g, 1.53 mmol), and (R)-2-methyl-CBS-oxazaborolidine (0.098 g, 0.35 mmol) in toluene (6 mL) was added a solution of distilled catecholborane (0.254 g, 2.39 mmol) in toluene (1 mL) over 15 minutes, then stirred for another 45 minutes. The reaction was quenched with saturated sodium carbonate solution and stirred at room temperature for 15 minutes. Product extracted with EtOAc and organic layer washed with saturated sodium carbonate (3×), brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 25% EtOAc/Hex) to give product contaminated with (S)-ethyl 2-(2-bromo-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)-2-hydroxyacetate. LCMS-ESI+: calc'd for C13H12ClF3NO6S2: 434.0 (M+H+); Found: 433.9 (M+H+).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].F[C:11]1[C:16]([CH3:17])=[C:15]([I:18])[CH:14]=[CH:13][N:12]=1>O1CCCC1>[CH:1]1([O:7][C:11]2[C:16]([CH3:17])=[C:15]([I:18])[CH:14]=[CH:13][N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: Cc1c(I)ccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(I)ccnc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyclohexanol (0.501 g) in tetrahydrofuran (3.5 mL) was treated with NaH (0.1 g) until gas evolution ceased. 2-Fluoro-4-iodo-3-methylpyridine (0.237 g) in tetrahydrofuran (1.5 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours and was quenched with ice-water. The resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC, and was eluted with petroleum ether to provide the title compound.
Reaction SMILES: [OH-].[Na+].BrBr.[C:5]([C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=1)/[CH:11]=[CH:12]/[C:13]1[N:21]([CH3:22])[C:20]2[C:19](=[O:23])[N:18]([CH2:24][CH3:25])[C:17](=[O:26])[N:16]([CH2:27][CH3:28])[C:15]=2[N:14]=1)(=[O:7])C.S([O-])([O-])(=[O:34])=S.[Na+].[Na+].Cl>O1CCOCC1.O>[CH2:24]([N:18]1[C:19](=[O:23])[C:20]2[N:21]([CH3:22])[C:13](/[CH:12]=[CH:11]/[C:10]3[CH:29]=[CH:30][CH:31]=[C:8]([C:5]([OH:7])=[O:34])[CH:9]=3)=[N:14][C:15]=2[N:16]([CH2:27][CH3:28])[C:17]1=[O:26])[CH3:25]
Reactant: CCn1c(=O)c2c(nc(/C=C/c3cccc(C(C)=O)c3)n2C)n(CC)c1=O
Reactant: O=S([O-])([O-])=S
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCn1c(=O)c2c(nc(/C=C/c3cccc(C(=O)O)c3)n2C)n(CC)c1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 84 %

Procedure:
Sodium hydroxide (432 mg, 10.8 mmol) and bromine (0.13 ml, 2.523 mmol) were added to water (3 ml) under ice-cooling, followed by addition of dioxane (3 ml). The mixture was slowly added to a suspension of 300 mg (0.819 mmol) of Compound 24 obtained in Example 23 in 3 ml of dioxane under ice-cooling, and the resulting mixture was stirred at room temperature for 3.5 hours. After ice-cooling, a 5% aqueous solution of sodium thiosulfate was added thereto, and the mixture was acidified with 2N HCl. The precipitated crystals were collected by filtration, and recrystallized from ethanol/water to give 254 mg (yield 84%) of Compound 25 as pale yellow needles.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1.[NH2:31][CH2:32][C@@H:33]([OH:36])[CH2:34][OH:35]>C1COCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[S:22][CH:23]=[C:19]([CH2:18][S:17][C:4]3[C:5]([C:15]#[N:16])=[C:6]([C:10]4[S:14][CH:13]=[N:12][CH:11]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:31][CH2:32][C@@H:33]([OH:36])[CH2:34][OH:35])[N:3]=3)[N:20]=2)=[CH:25][CH:26]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Reactant: NC[C@@H](O)CO
Solvent: C1CCOC1
Product: N#Cc1c(NC[C@@H](O)CO)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg (0.206 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile, together with 38 mg (0.411 mmol) of (2R)-3-aminopropane-1,2-diol, were dissolved in 1.5 ml of THF. The mixture was stirred at room temperature for two hours, and the product was then purified by preparative HPLC (acetonitrile/water: 10:90→95:5, 0.1% TFA added). This gave 64 mg (58%/0 of theory) of the target compound.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35]C(=O)OC(C)(C)C)[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH2:35])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NC(=O)OC(C)(C)C)C4)n3)c3cc(F)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](N)C4)n3)c3cc(F)cnc32)cc1
Reaction time: 0.08 h

Procedure:
tert-Butyl N-[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolyl sulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]carbamate, 44d, (3.7 g, 6.2 mmol) was dissolved in dichloromethane (105 mL) and treated with trifluoroacetic acid (31 mL). After 5 minutes, the volatiles were evaporated under reduced pressure, and the resulting residue was treated with 1N NaOH (75 mL). The resulting precipitate was collected by filtration, washed with water (3×30 mL) and vacuum dried to provide 2.7 g of (1s, 3R)—N1-[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]cyclohexane-1,3-diamine as a white solid.
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[OH-].[Na+].[NH2:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCOCC1.O>[O:1]([CH2:8][C:9]([NH:18][CH:19]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:27]([OH:29])=[O:28])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=C(COc1ccccc1)NC(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6.6 mmol (1.0 g) of phenoxyacetic acid in 15 ml of dioxane is treated with 49.3 mmol (3.6 ml) of thionyl chloride. The reaction mixture is stirred at room temperature for 2 hours and then concentrated. The residue, taken up in 10 ml of dichloromethane, and 7.9 mmol (0.3 g) of sodium hydroxide in 10 ml of water are added in succession to a solution of 7.6 mmol (1.25 g) of phenylalanine and 7.6 mmol (0.3 g) of sodium hydroxide in 10 ml of water, the temperature being maintained at 10° C. The reaction mixture is then stirred for 1 hour at room temperature. After decanting, the aqueous phase is washed with dichloromethane, and then rendered acidic to pH=2 with a dilute hydrochloric acid solution. The precipitate that forms is filtered off and recrystallised from water to yield the expected product.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([NH:13][NH2:14])=[O:12])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](O)=O)[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24]2[O:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]4[N:4]=[CH:3][N:2]([CH3:1])[C:6]=4[CH:7]=3)=[N:13][N:14]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)CCc1cccc(F)c1
Reactant: Cn1cnc2ccc(C(=O)NN)cc21
Product: Cn1cnc2ccc(-c3nnc(CCc4cccc(F)c4)o3)cc21
Yield: 66 %

Procedure:
In the same manner as in Example 14 and using 1-methyl-1H-benzimidazole-6-carbohydrazide instead of 1H-benzotriazole-5-carbohydrazide and 3-(3-fluorophenyl)propionic acid instead of 3-(3-cyanophenyl)propionic acid, the title compound (yield 66%) was obtained as colorless crystals.