Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH2:45]([NH2:49])[CH:46]([CH3:48])[CH3:47]>CN(C=O)C>[CH2:45]([NH:49][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:22])[CH:46]([CH3:48])[CH3:47]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CC(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCC(C)C)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 Mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and isobutylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-(isobutyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:25]C)=[C:10]([N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:11]=1.C(=O)(O)[O-].[Na+].[OH-].[Na+]>ClCCl>[CH:23]1[C:24]2[N:12]([C:10]3[CH:11]=[C:6]([F:5])[CH:7]=[CH:8][C:9]=3[OH:25])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(F)cc1-n1c2ccccc2c2ccccc21
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(F)cc1-n1c2ccccc2c2ccccc21
Temperature: -78 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
A 1.0 M boron tribromide solution in dichloro-methane (60 mL, 60 mmol, 3 equiv) was added dropwise over 30 minutes at −78° C. to a solution of compound 4 (5.8 g, 20 mmol, 1 equiv) in dichloromethane (60 mL). The reaction was stirred at −78° C. for 4 hours, when 1H-NMR indicated that the reaction was complete. The reaction was poured into saturated sodium bicarbonate (100 mL) and the pH adjusted to 8 with 10% sodium hydroxide. The layers were separated and the aqueous phase was extracted with dichloro-methane (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified over silica gel (100 g), eluting with a gradient of 60 to 100% dichloromethane in heptanes. The product containing fractions were combined, concentrated under reduced pressure and triturated with 20% methyl tert-butyl ether in heptanes (10 mL) to give compound 5 (4.3 g, 78% yield) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[OH:5][CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1>C1COCC1>[OH:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:2][C:3]#[N:4])[CH2:7]1
Reactant: OC1CCCNC1
Reactant: N#CCBr
Solvent: C1CCOC1
Product: N#CCN1CCCC(O)C1
Temperature: 47.5 °C

Procedure:
BrCH2CN (3.19 g, 25.82 mmol) was added dropwise to a solution of 3-hydroxypiperidine (6.53 g, 64.55 mmol) in dry THF (25 mL) under N2, maintaining the temperature between 45-50° C. Following addition of BrCH2CN, the solution was refluxed for 30 min., before allowing the solution to cool down to room temperature. The solvent was removed in vacuo and the residual oil was purified by flash chromatography using CH2Cl2:CH3OH (9:1) as eluent. The title compound was obtained as a straw-coloured oil (3.04 g, 83%). δh (250 MHz; CDCl3); 1.9-2.15 (m, 3H, CH2CH2CH2, 1×CH2CH2CHOH), 2.25 (m, 1H, 1×CH2CH2CHOH), 2.55 (d, OH), 2.85-3 (m, 3H, NCH2CH2, 1×NCH2CH), 3.1 (2×d, 1H, 1×NCH2CH), 3.9 (s, 2H, NCH2CN) and 4.3 (m, 1H, CH2CHOH); FAB MS, m/z (M+H)+141.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][C:28]([CH3:42])([O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH3:42][C:28]1([O:31][Si:32]([CH:33]([CH3:35])[CH3:34])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH2:29][CH2:30][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27]1
Reactant: CC(C)[Si](OC1(C)CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[Si](OC1(C)CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of Intermediate A (111 mg, 0.680 mmol) in DMF (2 mL) was added NaH (60% in oil, 68 mg, 1.70 mmol) and the mixture stirred at RT for 20 min, before Intermediate 79d (230 mg, 0.566 mmol) was added. This mixture was stirred at 60° C. for 1 h. The cooled reaction mixture was diluted with EtOAc (100 mL), washed with water (2×), brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (160 mg, 51%). LCMS (Method 1): Rt 3.06 min, m/z 550 [MH+].
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[F:15].Cl>[OH-].[Na+]>[CH2:5]([O:4][C:2](=[O:3])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[F:15])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(O)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Nc1ccc(O)cc1F
Temperature: 80 °C

Procedure:
Ethyl chloroformate (0.37 ml, 3.9 mmol) was added to a stirring solution of 4-amino-3-fluorophenol (0.5 g, 3.9 mmol) in 2 ml of 10% NaOH. The reaction mixture was heated at 80° C. for 30 min. After cooling, the solution was acidified with hydrochloric acid to give the product. 1H NMR (400 MHz, DMSO-d6): 1.20 (3H, t, J=7.0 Hz), 4.06 (2H, q, J=7.0 Hz), 6.53-6.59 (2H, m), 7.16-7.21 (1H, m), 8.79 (1H, s), 9.72 (1H, s).
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[K+].S(C1C=CC(C)=CC=1)([O:28][CH3:29])(=O)=O>CN(C=O)C.ClCCl>[CH3:29][O:28][C:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]=1[S:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(SC2CN(c3ccccc3)c3ncccc32)cc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(Sc2ccccc2)c2cccnc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 25.1 %

Procedure:
Add 1,3-dihydro-N-phenyl-3-(phenylthio)-2H-pyrrolo(2,3-b)pyridine (4.0 g, 12.6 mmole) portionwise to potassium hydride (KH) (1.73 g of 35 weight-percent KH in oil, washed with hexane, 15.1 mmole) in dry DMF (50 mL) at 0° C. under a nitrogen atmosphere. Stir for 45 minutes at 0° C. Add methyl tosylate(3.04 g, 16.3 mmole), and warm the reaction mixture up to room temperature slowly. Stir for 16 hours at room temperature. Remove DMF by high vacuum distillation. Add saturated aqueous NH4Cl (150 mL) and extract with ethyl acetate. Wash the organic extracts with saturated aqueous NaCl, dry with MgSO4, filter and rotoevaporate to give an oil. Dissolve oil in dichloromethane and chromatograph on silica gel, eluting with ethyl acetate:hexane (1:6). Combine appropriate fractions and concentrate under reduced pressure to give an oil. Crystallize the oil with diethyl ether-hexane to give the title compound as a white solid (1.05 g, m.p.=86°-87.5° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][CH:35]([C:37]([O:39]CC)=[O:38])[CH3:36])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[Cl:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.[OH-].[K+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][CH:35]([C:37]([OH:39])=[O:38])[CH3:36])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[Cl:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1
Reactant: CCOC(=O)C(C)COc1ccc(Br)cc1C1CC(=O)NC(c2cc(Cl)ccc2Cl)C12C(=O)Nc1cc(Cl)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(COc1ccc(Br)cc1C1CC(=O)NC(c2cc(Cl)ccc2Cl)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Yield: 9.1 %

Procedure:
Racemic (2′R,3S,4′R)-4′-[5-bromo-2-(2-ethoxycarbonyl-2-methyl-ethoxy)-phenyl]-6-chloro-2′-(2,5-dichloro phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (150 mg, 0.22 mmol) was dissolved in THF (5 mL). Then aqueous solution (1 mL) of KOH (50 mg, 0.88 mmol) was added. The mixed solution was refluxed for 1 h. The mixture was cooled, concentrated and acidified to “pH” 2-3. The solution was concentrated and the residue was purified by Prep-HPLC to obtain a white solid (13 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:7][C:6]([N:15]([CH3:24])[C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O>[CH2:16]([N:15]([CH3:24])[C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:8][C:3]([N:2]([CH3:31])[CH3:1])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][CH2:5]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(C)C1(c2ccccc2)CCC(c2ccccc2)(N(C)C(=O)c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(c2ccccc2)(N(C)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
The title compound from step 1 (160 mg, 0.387 mmol) was dissolved in abs. THF (15 mL) and mixed with LiAlH4 (29 mg, 0.775 mmol) in argon. The batch was boiled for 7 h with reflux and then cooled to room temperature. THF (5 mL) and H2O (5 mL) were added to the batch with ice cooling and subsequently stirred for 30 min. The batch was filtered over a fritted glass filter with diatomaceous earth and subsequently rinsed with dichloromethane (50 mL). The combined filtrates were concentrated to low volume in vacuum.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)=[N:5][N:6]=1.[CH2:18]([C:20]1[C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=[CH:22][C:21]=1[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N#N>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:9]1[CH:8]=[C:7]([C:4]2[S:3][C:2]([C:25]3[C:20]([CH2:18][CH3:19])=[C:21]([CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:22]=[CH:23][CH:24]=3)=[N:6][N:5]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Oc1ccc(-c2nnc(Br)s2)cc1Cl
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cccc1C1CCNCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(-c2nnc(-c3ccc(OC(C)C)c(Cl)c3)s2)cccc1C1CCNCC1
Reaction time: 0.33 h
Yield: 11.9 %

Procedure:
To a solution of 2-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazole (D10) (635 mg, 1.903 mmol), 4-[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (D119) (600 mg, 1.903 mmol) and Pd(Ph3P)4 (220 mg, 0.190 mmol) in N,N-Dimethylformamide (DMF) (5 mL) and Water (1.000 mL) was added tripotassium phosphate (1616 mg, 7.61 mmol). The solution was charged with N2 and sealed, irritated in Microwave at 120° C. for 20 min. This solution was purified by reverse phase chromatography to afford 4-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]piperidine (D120) (100 mg). MS (ES): C24H28ClN3OS requires 441.1. found 442.1 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[C:29]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:3]1.N12CCCN=C1CCC[CH2:42][CH2:41]2.ICC>CN(C)C=O>[CH2:41]([O:33][C:32](=[O:34])[CH2:31][CH2:30][C:4]1([CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:3][C:2](=[O:1])[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[C:29]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5]1)[CH3:42]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2=O
Solvent: CN(C)C=O
Solvent: CCI
Product: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)O)(CCC(=O)OCC)CC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the titled product of Example 43 (676 mg, 1.25 mmol) in 5 ml of dimethylformamide (DMF) was added 190 mg (1.25 mmol) of 1,8-diazabicyclo (5.4.0)undec-7-ene followed by 585 mg (3.75 mmol) of iodoethane. After stirring overnight at room temperature, the solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2. The solution was then washed with 3N hydrochloric acid, dried (Na2SO4), filtered, and the solvent removed on a rotary evaporator. The residue was chromatographed on a silica gel column. Elution with 35% ethyl acetate/61.5% hexane/2.5% acetic acid as eluent produced the title product which was crystallized from 3:1 hexane:ethyl acetate to give 183 mg, m.p. 83.5°-84.5° C.
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[C:12]([OH:19])[CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:20][C:21]1[C:26]([O:27][Si](C(C)(C)C)(C)C)=[CH:25][CH:24]=[CH:23][C:22]=1[C@@H:35](O)[CH3:36]>>[N:1]1([C:10]2[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[C:12]([O:19][C@@H:35]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([OH:27])[C:21]=3[Cl:20])[CH3:36])[CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C[C@H](O)c1cccc(O[Si](C)(C)C(C)(C)C)c1Cl
Reactant: COC(=O)c1sc(-n2cnc3ccccc32)cc1O
Product: COC(=O)c1sc(-n2cnc3ccccc32)cc1O[C@H](C)c1cccc(O)c1Cl
Yield: 73.3 %

Procedure:
Title compound (2.2 g) was prepared from methyl 5-(1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarboxylate (J. Heterocyclic Chem., 1987, 24, 1301-1303) (1.9 g, 7.0 mmol) and (1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)ethanol (Intermediate 17, 2.0 g, 7.0 mmol) using a procedure analogous to Intermediate 2, Step C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([C:10]#[N:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:18]=[C:17]([NH:19][CH:20]2[CH2:22][CH2:21]2)[C:16]2=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:15]2[N:14]=1.[CH3:28][S:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])=[O:30].COC(OC)OC.C(O)(=O)C.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO.C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[C:7]([CH2:8][N:35]2[CH2:36][CH2:37][N:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:33][CH2:34]2)=[CH:6][C:5]([C:10]#[N:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:18]=[C:17]([NH:19][CH:20]2[CH2:22][CH2:21]2)[C:16]2=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:15]2[N:14]=1
Reactant: N#Cc1cc(C=O)c(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: COC(OC)OC
Product: CS(=O)(=O)N1CCN(Cc2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.2 %

Procedure:
A solution of 2-((2-chloro-5-cyano-3-formylphenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 400) (18 mg, 0.048 mmol), 1-(methylsulfonyl)piperazine (9.5 mg, 0.058 mmol), trimethylorthoformate (0.027 mL, 0.242 mmol), and acetic acid (3 μL, 0.05 mmol) in a mixture of MeOH (0.5 mL) and DCM (0.5 mL) was stirred at room temperature for 15 min. A solution of sodium cyanoborohydride (0.097 mL, 1M in THF mL, 0.097 mmol) was added and the reaction was left stirring at room temperature overnight. Additional sodium cyanoborohydride (0.097 mL, 1M in THF mL, 0.097 mmol) was added and the reaction was left stirring for 1 day. A saturated aq. solution of NaHCO3 solution was added and, after 15 min, this was extracted with a mixture of 5% MeOH in DCM (5×). The combined organic extracts were dried with sodium sulfate and the solvent was removed. Silica gel radial chromatography of the residue eluting with DCM containing 0 to 2% MeOH afforded the title compound (7.9 mg) as foam.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8](I)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Si:12]([C:16]#[CH:17])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>[Cu](I)I>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:17]#[C:16][Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ccc(I)cc1C(=O)O
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(N)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
2-amino-5-iodobenzoic acid (500 mg, 1.9 mmol, 1 eq.) was dissolved in nitrogen-degassed THF (10 mL) at room temperature. TMS-acetylene (0.34 mL, 2.5 mmol, 1.3 eq.), nitrogen-degassed triethylamine (0.8 mL, 5.7 mmol, 3 eq.), dichloro-bis(triphenylphosphine)palladium(II) (267 mg, 0.4 mmol, 0.2 eq.), and copper iodide (145 mg, 0.8 mmol, 0.4 eq.) were added, in order, to the reaction in the dark. The reaction was then stirred at room temperature for 20 minutes. The solvent was evaporated, and the residue was purified on silica column (DCM/MeOH, 39:1→19:1) to result in 315 mg (71%) of the title compound as a dark orange solid. 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J=1.7, 1H, Ar—H), 7.37 (dd, J=1.8, 8.6, 1H, Ar—H), 6.57 (d, J=8.6, 1H, Ar—H), 0.22 (s, 9H, SiC3H9). 13C NMR (126 MHz, CDCl3) δ 173.11 (COOH), 151.15 (C—Ar), 138.41 (C—Ar), 136.64 (C—Ar), 116.94 (C—Ar), 111.06 (C—Ar), 109.23 (C—Ar), 104.98 (CSi(CH3)3), 92.02 (CCSi(CH3)3), 0.29 (Si(CH3)3). Exact Mass, 233.09. 231.7418 [M−H]−, 233.7569 [M+H]+.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]([C:12]([OH:14])=O)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:17]([N:24]=[C:25]=[S:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(C)C>[C:18]1([CH2:17][N:24]2[C:12](=[O:14])[CH:10]([CH2:9][S:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[NH:11][C:25]2=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: S=C=NCc1ccccc1
Reactant: N[C@@H](CSCc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C1C(CSCc2ccccc2)NC(=S)N1Cc1ccccc1
Yield: 8.9 %

Procedure:
When 2 g of S-benzylcysteine (0.0095 mole), 0.41 g of sodium hydroxide (0.0104 mole) and 1.55 g of benzylisothiocyanate (0.0104 mole) was treated according to the procedure for the preparation of the compound of Example 2, 0.289 g of pure title compound was obtained by crystallization from isopropyl alcohol: 1H NNR was consistent with the assigned structure for the thiohydantoin.
Reaction SMILES: [NH2:1][C@H:2]([CH3:19])[C@:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C@H:2]([CH3:19])[C@:3]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])([OH:10])[CH2:4][N:5]2[CH:9]=[N:8][CH:7]=[N:6]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C[C@@H](N)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)[C@](O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
Following the general sulfonylation procedure explained in example 1 and using (2R*,3R*)-3-amino-2-(2,4-dichlorophenyl)-l-(1H-1,2,4-triazol-1-yl)butan-2-ol, prepared as described in EP 332,387, and 4-chlorobenzenesulfonyl chloride, the title product is obtained in similar yield.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:3]=1.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25])([O-:18])=[O:17].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:5]=[CH:6][N:7]=1)([O-:18])=[O:17]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: Clc1cc(NCc2cccnc2)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1Nc1cc(NCc2cccnc2)ncn1
Temperature: 100 °C
Yield: 34.2 %

Procedure:
A degassed mixture of (6-chloro-pyrimidin-4-yl)-pyridin-3-ylmethyl-amine (300 g, 1.36 mmol), 2-nitro-phenylamine (188 g, 1.36 mmol), Pd2(dba)3 (128 g, 0.14 mmol), Xantphos (161 g, 0.28 mmol) and Cs2CO3 (913 g, 2.8 mmol) in toluene (10 mL) was heated at 100° C. for 4 hours. The reaction was concentrated, and the residue was purified by flash chromatography on silica to obtain the title compound (150 mg, yield: 34%). MS (ESI): 323 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[N:9]([CH3:31])[C:10](=[O:30])[C:11]([O:28][CH3:29])=[C:12]2[C:17]=1[CH2:16][CH2:15][N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1)[C:13]2=[O:27])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CN(C=O)C>[C:1]([O:5][C:6](=[O:32])[N:7]([C:8]1[N:9]([CH3:31])[C:10](=[O:30])[C:11]([O:28][CH3:29])=[C:12]2[C:17]=1[CH2:16][CH2:15][N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1)[C:13]2=[O:27])[S:36]([CH3:35])(=[O:38])=[O:37])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c2c(c(NC(=O)OC(C)(C)C)n(C)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c2c(c(N(C(=O)OC(C)(C)C)S(C)(=O)=O)n(C)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl-[6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]carbamate (0.49 g, 1.07 mol) and sodium hydride (54 mg, 1.34 mmol; 60% dispersion in oil) in anhydrous DMF (6 mL) was stirred at 0° C. for 30 minutes. Methanesulfonyl chloride (0.18 g, 1.61 mmol) was added, and the mixture was allowed to warm up slowly to room temperature. The reaction mixture was quenched with aqueous acid and diluted with dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatograph on silica gel eluting with a mixture of 1% methanol in dichloromethane. Collection and concentration of appropriate fractions provided the intermediate tert-butyl-[6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl](methylsulfonyl)carbamate (ES MS M+1=544). A solution of the above intermediate sulfonylcarbamate (281 mg, 0.52 mmol) and trifluoroacetic acid (5 mL) in anhydrous dichloromethane (5 mL) was stirred at room temperature for 10 minutes. The product mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and aqueous acid. The organic extract was washed dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound. ES MS M+1=444