Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:14][C:15]([CH3:20])([CH3:19])[C:16](=[O:18])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr.[OH-].[Na+]>C(O)(=O)C.Cl>[CH:1]([N:14]1[CH2:17][C:16](=[O:18])[C:15]1([CH3:20])[CH3:19])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(C)(C)NC(c1ccccc1)c1ccccc1
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(C)C(=O)CN1C(c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
Into 3-(benzhydrylamino)-3-methylbutan-2-one (6.5 g) in acetic acid (20 mL), HCl gas was blown up to saturation, and bromine (1.25 mL) was added dropwise thereto, followed by stirring for 3 hours. 20% Aqueous sodium hydroxide was added to the reaction mixture, and thereby pH of the mixture was adjusted at 14 or higher, followed by partitioning by use of carbon tetrachloride. The organic layer was washed with water. The solvent was evaporated under reduced pressure, and to the residue, N,N-dimethylformamide (30 mL) and saturated aqueous sodium hydrogencarbonate (7 mL) were added, followed by stirring for 3 minutes. The reaction mixture was partitioned between water and carbon tetrachloride. The organic layer was washed twice with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, and the residue was purified through silica gel column chromatography, to thereby give 1-benzhydryl-2,2-dimethylazetidin-3-one as a solid (754 mg, 12%).
Reaction SMILES: [C-]#N.[Na+].[CH2:4]([N:7]1[C:16]([C:17]#[N:18])=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:26]C)[CH:13]=2)[C:8]1=[O:28])[CH:5]=[CH2:6].Cl>CS(C)=O>[CH2:4]([N:7]1[C:16]([C:17]#[N:18])=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:26])[CH:13]=2)[C:8]1=[O:28])[CH:5]=[CH2:6]
Reactant: C=CCn1c(C#N)c(-c2cccc(F)c2)c2cc(OC)ccc2c1=O
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: C=CCn1c(C#N)c(-c2cccc(F)c2)c2cc(O)ccc2c1=O
Temperature: 150 °C

Procedure:
Sodium cyanide (3.3 g, 67.2 mmol) was added to a suspension of 2-Allyl-4-(3-fluorophenyl)-6-methoxy-1-oxo-1,2-dihydroisoquinoline-3-carbonitrile (7.5 g, 22.4 mmol) in DMSO (100 mL). The reaction mixture was heated to 150° C. for 18 h. The reaction was cooled to room temperature and diluted with ice water (100 mL). This was acidified to a pH of 5 with 6M HCl. The brown precipitate was filtered and washed with ether to yield the title compound as a brown solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]([O:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:24])[N:22]=2)[CH:17]([NH:25][CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[CH2:16][CH:15]1[CH2:41][CH3:42])=[O:13])([CH3:10])[CH3:9].N1C=CC=CC=1>ClCCl>[CH:8]([O:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:24])[N:22]=2)[CH:17]([N:25]([C:1](=[O:3])[CH3:2])[CH2:26][C:27]2[CH:28]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=2)[CH2:16][CH:15]1[CH2:41][CH3:42])=[O:13])([CH3:10])[CH3:9]
Reactant: CCC1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C)nc2N1C(=O)OC(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1CC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2ccc(C)nc2N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
Inject acetic anhydride (0.250 ml, 2.65 mmol) dropwise to a solution of crude 4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-7-methyl-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid isopropyl ester (0.090 g, 0.199 mmol) and pyridine (0.250 ml, 3.10 mmol) in dichloromethane (1 ml) at room temperature. Stir the mixture at room temperature for 16 h. Evaporate the solvents and purify using silica gel column chromatography (gradient eluent, 0-40% ethyl acetate in hexane) to provide the title compound (0.0650 g, 66%). MS (ES+): 546 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>Cl.[OH-].[Na+]>[Cl:9][C:5]1[CH:6]=[C:7]2[C:2]([NH:1][C:16](=[O:20])[C:17](=[O:18])[NH:8]2)=[C:3]([C:10]([F:13])([F:11])[F:12])[CH:4]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(Cl)cc(C(F)(F)F)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2cc(Cl)cc(C(F)(F)F)c2[nH]c1=O
Temperature: 25 °C
Yield: 50.5 %

Procedure:
A mixture of 2,3-diamino-5-chlorobenzotrifluoride (180 mg, 0.86 mmol) and oxalic acid dihydrate (108 mg, 0.86 mmol, used as received) in 2N HCl (4 mL) was refluxed at 120°-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the liquid layer was removed. The yellow solid was washed by cold water (2×2 mL), collected by filtration, and dried at 60° C. for 2 h, affording 136 mg of crude title compound (53%) as a yellow powder. The crude title compound was dissolved in 1N NaOH (6 mL) and filtered. The filtrate was acidified to pH=6, affording 115 mg of title compound. Recrystallization from DMSO/H2O gave 95 mg of pure title compound (37%) as yellow microcrystals. Mp: 302°-4° C. (dec. from 295° C.). IR (KBr, cm-1) 3401, 3255, 1754, 1694, 1528. 1H NMR (DMSO-d6): δ7.374 (d, 1H, J=1.8 Hz); 7.474 (d, 1H, J=1.8 Hz); 11.347 (s, 1H); 12.215 (s, 1H). HRMS: calcd for C9H4ClF3N2O2 (M+) m/z: 263.9912; found: 263.9909.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9](=[O:22])[CH2:10][CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3]C=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>CCOC(C)=O.O.CCOCC>[OH:15][CH2:13][CH2:12][CH:11]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:10][C:9]([N:8]([CH3:23])[C:7]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:1]=1)=[O:22]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(CC(=O)NCc1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C(=O)CC(CCO)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
Beta-[2-[(phenyl)methylamino]-2-oxoethyl]benzenepropanoic acid (11.5 g) in EtOAc (225 mL) was treated with carbonyldiimidazole (11.68 g) and N,N-dimethylaminopyridine (1.0 g). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for two hours. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (9.74 g) in H2O (150 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was then diluted with Et2O and washed with 1N HCl (100 mL), sat. NaHCO3 (100 mL) and water (100 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound (10.4 g).
Reaction SMILES: C([O:8][C:9]1[C:14]([NH:15]C(=O)OCC2C=CC=CC=2)=[CH:13][N:12]=[C:11]([N:26]2[CH:30]=[CH:29][CH:28]=[N:27]2)[N:10]=1)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[NH2:15][C:14]1[C:9]([OH:8])=[N:10][C:11]([N:26]2[CH:30]=[CH:29][CH:28]=[N:27]2)=[N:12][CH:13]=1
Reactant: O=C(Nc1cnc(-n2cccn2)nc1OCc1ccccc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cnc(-n2cccn2)nc1O
Yield: 93 %

Procedure:
Benzyl 4-(benzyloxy)-2-(1H-pyrazol-1-yl)pyrimidin-5-ylcarbamate, 3-d, (1.96 g, 4.9 mmol) was hydrogenated with hydrogen ballon in THF (20 ml) and Pd/C (200 mg) at room temperature for 12 hours. The mixture was filtered through a celite pad and the filtrate was concentrated under vacuum to provide the compound, 3-e (0.8 g, 93%). 1H NMR (DMSO-d6, 300 MHz): δ 8.39 (s, 1H), 7.80 (s, 1H), 7.20 (s, 1H), 6.56 (m, 1H), 5.00 (br, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:40])([F:39])[F:38])[CH2:33][CH2:32]3)=[O:30])=[CH:25][CH:24]=2)[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[C:10]1=[O:21].C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>ClCCl>[Cl:22][C:6]1[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]3[CH2:36][CH2:35][CH:34]([C:37]([F:38])([F:40])[F:39])[CH2:33][CH2:32]3)=[O:30])=[CH:25][CH:24]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][S:49]([CH3:48])(=[O:51])=[O:50])[CH2:16][CH2:15]2)[C:10]1=[O:21]
Reactant: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN([C@H]4CC[C@H](O)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve (R)-3-[3,5-Dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-trans-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one (Preparation 23) (0.419 g, 0.70 mmol) in 10 ml of dry dichloromethane at 0° C. Add triethylamine (0.18 ml, 1.41 mmol) followed by methanesulfonyl chloride (0.06 ml, 0.77 mmol). Stir at room temperature for 5 hours. Quench with 1N HCl and extract with ethyl acetate. Wash the extract with 1N HCl, NaHCO3 and brine. Dry over magnesium sulfate, filter, and concentrate. Filter through a short silica plug to receive 0.45 g (95%) of the title compound: Mass spectrum (apci) m/z=675 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>CN(C=O)C.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:15]([C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(C)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=CCc1cc(C)ccc1C(=O)OC
Temperature: 90 °C
Yield: 79.5 %

Procedure:
A mixture of methyl 2-bromo-4-methylbenzoate (500 mg, 2.183 mmol), allyltributylstannane (0.744 mL, 2.401 mmol), lithium chloride (185 mg, 4.37 mmol) in DMF (1 mL), acetonitrile (10 mL) was added bis(triphenylphosphine)palladium(ii) dichloride (77 mg, 0.109 mmol). It was then degassed for 2 min, then filled with N2. After heating at 90° C. for 16 h, it was quenched with NH4Cl, extracted with EtOAc. The organic layer was washed with KF solution, dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to isolate methyl 2-allyl-4-methylbenzoate (330 mg, 1.735 mmol, 79% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.95-7.77 (m, 1H), 7.21-6.99 (m, 2H), 6.19-5.85 (m, 1H), 5.22-4.91 (m, 2H), 3.89 (s, 3H), 3.76 (d, J=6.6 Hz, 2H), 2.39 (s, 3H).
Reaction SMILES: [Br:1][C:2]([Br:5])=[N:3][OH:4].[C:6](Cl)(=[O:9])[CH2:7][CH3:8].N1C=CC=CC=1>C(Cl)Cl>[C:6]([O:4][N:3]=[C:2]([Br:5])[Br:1])(=[O:9])[CH2:7][CH3:8]
Reactant: ON=C(Br)Br
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)ON=C(Br)Br
Yield: 0.1 %

Procedure:
To the mixture of dibromoformaldoxime (5 g, 24.63 mole) and propionyl chloride (2.31 g, 25 mole) in dry methylene chloride (30 ml) is slowly added dry pyridine (2 g, 25.5 mole) over 10 min at 0° to 5° C. with stirring. After addition the reaction mixture is stirred at 5° C. for 30 min and at 25° C. for another 30 min. The resultant suspension is diluted with methylene chloride and washed with water and brine. The organic layer is dried over MgSO4. Evaporation of solvent affords 5.44 g (85% of theory) of O-propionyldibromoformaldoxime as a light yellow liquid. NMR spectrum shows this to be the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[N:11](C)C)=[CH:4][CH:3]=1.Cl.[NH:16]([C:18]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][N:19]=1)N>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C:18]3[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][N:19]=3)[N:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CN(C)/C=C/C(=O)c1ccc(Br)cc1
Reactant: N#Cc1ccnc(NN)c1
Agent: Cl
Solvent: CO
Product: N#Cc1ccnc(-n2nccc2-c2ccc(Br)cc2)c1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A solution of (2E)-1-(4-bromophenyl)-3-(dimethylamino)prop-2-en-1-one (100 mg, 0.39 mmol) and 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (90 mg, 0.43 mmol, PREPARATION 3) in MeOH (10 mL) was heated under reflux conditions for 30 min and then cooled to rt. The solution was concentrated, and the residue was purified by flash column chromatography (hexanes:EtOAc=1:1) to give the title compound (108 mg, 85%) as an orange-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[N:12][OH:13])[CH2:7][CH2:6][CH2:5]2.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[S:20]([O:13][N:12]=[C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1)([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: ON=C1CCCc2cc(Br)ccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)ON=C2CCCc3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.5 %

Procedure:
To 6-bromo-3,4-dihydronaphthalen-1(2H)-one oxime (2.5 g, 10.41 mmol) in pyridine (5 mL) was added p-toluenesulfonyl chloride (2.184 g, 11.45 mmol) in one lot at room temperature. The reaction mixture was stirred at room temperature for 20 h. Ice cubes (˜10 g) were added to the flask and the contents stirred at room temperature for 30 min. The solid that separated out was filtered and washed with water (3×20 mL), dried over sodium sulfate and concentrated to yield 6-bromo-3,4-dihydronaphthalen-1(2H)-one O-tosyl oxime (3.92 g, 9.94 mmol, 95% yield) as light pink solid. The solid was azeotroped once with toluene (10 mL) and used for the subsequent reaction. MS M+1=395.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[C:15]([Br:16])=[C:14]2[C:10]([CH:11]=[N:12][N:13]2[CH2:17][C@@H:18]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH3:19])=[CH:9][CH:8]=1)C.[BH4-].[Na+].[Cl-].[Ca+2].[Cl-]>O1CCCC1.C(O)C>[CH2:24]([O:23][C:21](=[O:22])[NH:20][C@@H:18]([CH3:19])[CH2:17][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([O:6][CH2:5][CH2:4][OH:3])[C:15]=2[Br:16])[CH:11]=[N:12]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)COc1ccc2cnn(C[C@H](C)NC(=O)OCc3ccccc3)c2c1Br
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](Cn1ncc2ccc(OCCO)c(Br)c21)NC(=O)OCc1ccccc1
Yield: 81.2 %

Procedure:
To a solution of the acetate from Step B (0.90 g, 1.84 mmol) in a mixture of tetrahydrofuran (20 mL) and ethanol (20 mL) was added sodium borohydride (70 mg, 1.84 mmol) and calcium chloride (0.21 g, 1.84 mmol) with stirring. The suspension was stirred at ambient temperature for 1 h and more sodium borohydride (70 mg, 1.84 mmol) was added. The reaction was monitored by TLC until no starting material remained. The volatiles were evaporated and the residue mixed with water and extracted with ethyl acetate (3×50 mL). The combined extracts were dried over magnesium sulfate, filtered and evaporated to dryness. Chromatography on silica eluting with a gradient of 20% to 50% EtOAc/hexane gave a solid (0.67 g, 82%): mp 97-99° C.; LCMS (+APCI) 448, 450 (M+H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14](O)[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]([Cl:23])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCC2O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCC2Cl
Temperature: 25 °C

Procedure:
7-Benzenesulfonyl-chroman-4-ol (483 mg, 1.66 mmol) was dissoved in 10 mL toluene, and 182 uL (02.49 mmol) of thionyl chloride was added. The reaction was refluxed for two hours, and then cooled to room temperature. Solvent was removed under reduced pressure to yield 7-benzenesulfonyl-4-chloro-chroman (512 mg) as a crude oil. MS: 308 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)(=[O:5])=[O:4].[S-:20][C:21]#[N:22].[K+].BrBr.[ClH:26]>C(O)(=O)C.C(O)C>[ClH:26].[CH3:1][NH:2][S:3]([CH2:6][CH2:7][N:8]1[C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]([F:17])([F:19])[F:18])=[CH:13][C:14]=2[S:20][C:21]1=[NH:22])(=[O:4])=[O:5]
Reactant: N#C[S-]
Reactant: CNS(=O)(=O)CCNc1ccc(OC(F)(F)F)cc1
Agent: BrBr
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: CNS(=O)(=O)CCn1c(=N)sc2cc(OC(F)(F)F)ccc21

Procedure:
The procedure is as in Example 3, starting with N-methyl-2-(p-trifluoromethoxyanilino)ethanesulphonamide (3.5 g), potassium thiocyanate (4.7 g) and bromine (2.2 g) in acetic acid (30 cc). After 18 hours at a temperature in the region of 20° C., neutralization with 30% strength sodium hydroxide and extraction with ethyl acetate, a crude product is obtained, which product is converted to a hydrochloride by adding 4.2N ethereal hydrogen chloride (3 cc) in ethanol (25 cc) and recrystallized in absolute ethanol (50 cc). The N-methyl-2-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanesulphonamide hydrochloride thereby obtained (2.1 g) melts at 242° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[N:26]1([CH2:32][CH2:33][CH2:34]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:34][CH2:33][CH2:32][N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCN2CCOCC2)cc1
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCCN4CCOCC4)cc32)nc1-c1cccc(Cl)c1
Yield: 56.2 %

Procedure:
A mixture of 0.037 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 0.060 g (0.2 mmole) of toluene-4-sulfonic acid 3-morpholin-4-yl-propyl ester, 1 mL of dimethylformamide and 0.160 g (0.5 mmole) of cesium carbonate was heated at 100 degrees for 30 minutes. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 20:80-100:0) to give 0.028 g of 4-(3-chloro-phenyl)-2-[6-(3-morpholin-4-yl-propoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.30) as a white powder. MH+/Z=498
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:15][NH:16][C@H:17]1[CH2:22][N:21](C(OC(C)(C)C)=O)[C@H:20]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:19][CH2:18]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][NH:16][C@H:17]1[CH2:22][NH:21][C@H:20]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:19][CH2:18]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
TFA (600 mL) was added to a solution of (2S,5R)-1-tert-butyl 2-ethyl 5-((benzyloxy)amino)piperidine-1,2-dicarboxylate (263 g, 0.7 mol) in DCM (600 mL) at 20° C. The mixture was stirred at rt overnight and then concentrated in vacuum. The crude product was adjusted to pH 10 with sat. NaHCO3 solution, and then extracted with DCM three times. The combined organic layer was concentrated in vacuum and purified by silica gel column chromatography (20:1 DCM/MeOH) to afford (2S,5R)-ethyl 5-((benzyloxy)amino)piperidine-2-carboxylate (184.9 g, 95%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]([OH:24])[CH2:11][N:12]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>N1C=CC=CC=1>[C:25]([O:24][CH:10]([CH2:11][N:12]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:27])[CH3:26]
Reactant: COC(=O)CN(CC(O)CSc1ccc(Cl)cc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)CN(CC(CSc1ccc(Cl)cc1)OC(C)=O)c1ccccc1
Reaction time: 20 h

Procedure:
After 200 mg (0.00054 moles) of 1-(p-chlorophenylthio)-3-(N-carbomethoxymethyl-N-phenylamino)-2-propanol and 1 g of acetic anhydride were dissolved in 3 ml of pyridine and left to stand at room temperature for 20 hr, the reaction mixture mixture was poured into iced water and extracted with ether. The ether layer was washed with 10% hydrochloric acid and water and dried. Evaporation or ether under reduced pressure gave 190 mg (86.5%) of an oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([NH2:17])=[O:16])=[CH:4][N:3]=1.[Br:18]Br.C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>CC(O)=O.C1COCC1.[Zn]>[Br:18][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:5]([C:15]([NH2:17])=[O:16])=[CH:4][N:3]=[C:2]([Cl:1])[C:14]=3[C:13]=2[CH:12]=1
Reactant: BrBr
Reactant: NC(=O)c1cnc(Cl)c2c1[nH]c1ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NC(=O)c1cnc(Cl)c2c1[nH]c1ccc(Br)cc12
Reaction time: 1 h

Procedure:
To a suspension of 1-chloro-5H-pyrido[4,3-b]indole-4-carboxamide (Example 10 Step 3) in AcOH (0.15 M) at room temperature was added Br2 (10 equiv) to provide a homogeneous mixture. After standing at room temperature a precipitate formed, and after 1 h, a suspension of Zn powder (excess) in THF was added in a cold water bath. After a period of 10 min, the reaction mixture was poured over THF/EtOAc and saturated NaHCO3. After separation of the organic phase, the aqueous phase was extracted again with THF/EtOAc, and the combined organic phases were washed with brine, dried over MgSO4 and filtered. After evaporation of the organic solvents, the residue was purified by flash chromatography (10-70% EtOAc in hexanes) to provide the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH3:17])[C:15]([C:18]#[N:19])=[C:14](Br)[C:13]=3[CH3:21])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:22])[O:3]1.[CH3:24][Sn](C)(C)C.O>CN(P(N(C)C)(N(C)C)=O)C>[CH3:1][C:2]1([CH3:23])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH3:17])[C:15]([C:18]#[N:19])=[C:14]([CH3:24])[C:13]=3[CH3:21])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:22])[O:3]1
Reactant: Cc1c(Br)c(C#N)n(C)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Reactant: C[Sn](C)(C)C
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1c(C)c(-c2ccc3c(c2)C(C)(C)OC(=O)N3)n(C)c1C#N
Yield: 85.8 %

Procedure:
A solution of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-bromo-1,4-dimethyl-1H-pyrrole-2-carbonitrile (0.11 g, 0.29 mmol), PhCNPdCl(PPh3)2 (cat., 11 mg) and tetramethyltin (10 eq, 0.53 g, 2.9 mmol) in HMPA (3 mL) was heated to 110° C. for 5d. The solution was allowed to cool, poured into water (20 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layer was washed with brine, dried over MgSO4 and purified by flash column chromatography on silica gel eluting with 30% ethyl acetate/hexane to give 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,3,4-trimethyl-1H-pyrrole-2-carbonitrile (77 mg, 85%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 1.63 (s, 6H), 1.87 (s, 3H), 2.49 (s, 3H), 3.50 (s, 3H), 6.99 (d, 1H, J=8.2 Hz), 7.25 (dd, 1H, J=8.2, 1.4 Hz), 7.29 (s, 1H), 10.39 (s, 1H). MS (ESI (−)) 308 (M−H)−. Anal. calcd for C18H19N3O4, C, 69.9, H, 6.19, N, 13.6. Found, C, 68.8, H, 6.22, N, 12.9.