Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].II>CN(C=O)C>[OH:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(O)cc3)nc2c1
Temperature: 70 °C
Yield: 12 %

Procedure:
2-Amino-4,6-dimethoxy-benzamide (328 mg, 1.67 mmol), 4-hydroxybenzaldehyde (204 mg, 1.67 mmol), K2CO3 (231 mg, 1.67 mmol) and I2 (508 mg, 2.0 mmol) were mixed in DMF (10 mL) and the reaction mixture was heated at 70° C. for 5 h. It was cooled to room temperature and poured into crushed ice. The solid was collected and purified by column chromatography (silica gel 230-400 mesh; 5% methanol in CH2Cl2 as eluent) to give 2-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (60 mg, 12%), as an off-white solid. Selected data: MS (m/z): 299.05; MP 303-305° C.
Reaction SMILES: [C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N:47]=[N+:48]=[N-:49])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:42]=[CH:41][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[NH:49][N:48]=[N:47][N:40]=3)=[CH:35][CH:34]=2)[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(C#N)cc2)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 80 °C

Procedure:
A solution of 1000 mg (1.79 mmol) of methyl 4-{(3E)-4-{2-[(4-tert-butylbenzyl)oxy]phenyl}-2-[2-(4-cyanophenyl)ethyl]but-3-en-1-yl}benzoate in 10 ml of toluene is mixed with 2851 mg (24.7 mmol) of trimethylsilyl azide and 618 mg (2.47 mmol) of di-n-butyltin oxide and heated at 80° C. for 12 h. After cooling to room temperature, the mixture is washed with saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated to dryness. The resulting crude product is purified by chromatography on a silica gel column (mobile phase: cyclohexane/ethyl acetate 2:1→1:2). 648 mg (1.08 mmol, 60% of theory) of a colorless oil are obtained.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:2].[O:20]1CC[CH2:22][CH2:21]1>[Ni]>[C:21]([NH:2][CH2:1][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:20])[CH3:22]
Reactant: CCOC(=O)c1cc2ccc(OC)cc2n1CC#N
Reactant: C1CCOC1
Agent: [Ni]
Product: CCOC(=O)c1cc2ccc(OC)cc2n1CCNC(C)=O

Procedure:
Dissolve 0.34 g of the compound obtained in Step A in 10 ml of tetrahydrofuran and add a catalytic amount of Raney nickel and hydrogenate the reaction (10 bars) at ambient temperature for 24 hours. Filter over Celite and then evaporate. Take up the residue in 10 ml of tetrahydrofuran in the presence of 0.16 ml of triethylamine and, at 0° C. under argon, add dropwise 0.15 ml of acetic anhydride. Stir the reaction at ambient temperature for 22 hours. Evaporate, and take up the residue in ethyl acetate. Wash the organic phase with saturated aqueous sodium hydrogen carbonate solution and then with saturated aqueous sodium chloride solution and subsequently dry over sodium sulfate. Filter and evaporate in vacuo, and then purify the compound by column chromatography on silica gel using ethyl acetate as eluant. The title compound is isolated in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([CH3:15])[C:11]([O:13]C)=[O:12])=[O:8])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([CH3:15])[C:11]([OH:13])=[O:12])=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)NC(=O)c1ccc(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(NC(=O)c1ccc(Cl)s1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.80 g (15.3 mmol) methyl 2-[(5-chloro-thiophene-2-carbonyl)-amino]-propionate are suspended in 15.5 ml (15.5 mmol) 1-molar aqueous sodium hydroxide solution, combined with 15 ml of ethanol and then stirred for 4 hours at ambient temperature. After evaporation i. vac. the residue is combined with ice water, extracted with diethyl ether, the aqueous phase is poured into an ice/acetic acid mixture and the resulting precipitate is suction filtered. After washing with water the precipitate is dried at 60° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([CH3:9])[O:4][N:3]=1.[O:10]=[S:11]1(=[O:34])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([NH:20][C@@H:21]([CH2:26][C:27]2[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=2)[C:22]([O:24][CH3:25])=[O:23])=[N:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[O:10]=[S:11]1(=[O:34])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([NH:20][C@@H:21]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:8][CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:9])=[CH:29][CH:28]=2)[C:22]([O:24][CH3:25])=[O:23])=[N:12]1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC1=NS(=O)(=O)c2ccccc21
Reactant: Cc1noc(C)c1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OCc2c(C)noc2C)cc1)NC1=NS(=O)(=O)c2ccccc21
Temperature: 5 °C

Procedure:
(3,5-Dimethylisoxazol-4-yl)methanol (0.28 g, 1.5 mmol), methyl (2S)-2-[(1,1-dioxo-1,2-benzoisothiazol-3-yl)amino]-3-(4-hydroxyphenyl)propionate (0.36 g, 1 mmol) and triphenylphosphine (0.79 g, 3 mmol) were dissolved in tetrahydrofuran (2 ml). After cooling to 5° C., DEAD (0.52 g, 3 mmol) was added to the reaction mixture. The reaction was then stirred at room temperature for 18–24 h. THF was evaporated to obtain crude title product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.[B-](F)(F)(F)[CH2:60][CH2:61][C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63].[K+].C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1.O>[C:65]([O:64][C:62](=[O:63])[CH2:61][CH2:60][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH:3]=1)([CH3:68])([CH3:67])[CH3:66]
Reactant: CN1CCC(OC(c2cccc(Br)c2)c2nc3ccccc3s2)CC1
Reactant: CC(C)(C)OC(=O)CC[B-](F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCC(OC(c2cccc(CCC(=O)OC(C)(C)C)c2)c2nc3ccccc3s2)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A screw-cap tube is charged with 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (208 mg), palladium(II) acetate (3 mg), RuPhos® 6 (12 mg), potassium 3-trifluoroboratopropionate tert-butyl ester (118 mg), potassium carbonate (207 mg), water (2.5 mL) and toluene (2.5 mL). The tube is evacuated, filled with argon and sealed. After stirring at 120° C. overnight, the mixture is diluted with ethyl acetate and water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol from 100/0 to 95/5) to afford 3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}propionic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:16]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)cc1
Reaction time: 5 h
Yield: 87.5 %

Procedure:
4-Bromobenzoic acid (9.98 kg, 48 mol) was suspended in 40 kg of methanol. Sulfuric acid (2 kg, 20 mol) was added and the mixture was heated under reflux for approximately 5 hours. The mixture was cooled over 10 hours to -10° C. and allowed to stand for 5 hours giving a crystalline product. The product was isolated by filtration and the filter cake was washed with methanol (2×3 L). Drying gave methyl 4-bromobenzoate (9.97 kg, 42 mol), m.p. 78°-78.7° C.
Reaction SMILES: [CH3:1][N:2]([S:16]([CH3:19])(=[O:18])=[O:17])[C:3]1[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[OH-].[K+].I[CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C>[CH2:23]([N:7]1[C:8]2[C:4](=[C:3]([N:2]([CH3:1])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=2)[CH:5]=[CH:6]1)[CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)c1cc(N(C)S(C)(=O)=O)c2cc[nH]c2c1
Reactant: CCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCn1ccc2c(N(C)S(C)(=O)=O)cc(C(=O)O)cc21
Temperature: 70 °C
Reaction time: 72 h

Procedure:
To a mixture of methyl 4-[methyl(methylsulfonyl)amino]-1H-indole-6-carboxylate (0.437 g) in DMF (15 mL) was added potassium hydroxide (0.087 g) and iodobutane (0.34 mL). The mixture was heated to 70° C. for 6 h. then stirred at room temperature for 72 h. The mixture was partitioned between water and ethyl acetate, the layers were separated and the organic layer washed three times with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in methanol (5 mL) to which was added 1N NaOH (2 mL) and the mixture heated to 50° C. for 1 h. The mixture was cooled to room temperature and poured into water and washed with ether. The aqueous layer was acidified to pH 4 with 1N HCl and the product extracted into ethyl acetate which was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give 0.377 g of the title compound: 1H NMR (CDCl3) δ 0.973, 1.38, 1.87, 3.01, 3.45, 4.21, 6.71, 7.36, 7.82, 8.18.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:2]([C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)#[N:1]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(I)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.3 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 0.610 g) in dichloromethane (15 mL) was treated with Burgess' reagent (0.365 g) and the mixture was stirred at room temperature for 2 days. The reaction mixture was absorbed onto silica and purified by chromatography on silica eluting with 25% ethyl acetate in isohexane, then 50% ethyl acetate in isohexane to afford the sub-titled compounds (0.402 g) as white crystals.
Reaction SMILES: [C:1](=[O:7])([O-])[O:2][CH2:3][CH2:4]Cl.[CH2:8]1[CH:13]2[C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:12]2[CH2:11][CH2:10][N:9]1[CH2:27][CH2:28][O:29][CH2:30]C(O)=O.C(O)C>C(Cl)(Cl)Cl>[CH2:8]1[CH:13]2[C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:12]2[CH2:11][CH2:10][N:9]1[CH2:27][CH2:28][O:29][CH2:30][C:1]([O:2][CH2:3][CH3:4])=[O:7]
Reactant: O=C([O-])OCCCl
Reactant: O=C(O)COCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
0.11 g of chloroethyl carbonate was added to a solution of 0.5 g of 2-(1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepin-2-yl)ethoxyacetic acid (prepared as described in Example 2) in 10 ml of chloroform containing 2% by volume ethanol, whilst ice-cooling, and the mixture was stirred at room temperature for 1 hour. At the end of this time, it was washed with water, and the solvent was removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel eluted with ethyl acetate, to give 0.25 g of the title compound as a colorless oil. The infrared absorption spectrum of this compound is identical with that of the compound prepared as described in Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:42])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:37]([O:39]CC)=[O:38])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:42])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:37]([OH:39])=[O:38])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(N3CCOCC3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(=O)O)c2[nH]c3cc(N4CCOCC4)ccc3c12
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxylate (0.3539 g, 0.627 mmol) in THF (17.4 mL) and MeOH (5.8 mL) was added a solution of lithium hydroxide hydrate (0.105 g, 2.507 mmol) in water (3 mL). After 1 hr, the reaction was concentrated in vacuo. Water (12 mL) was added, and the solution was acidified with aqueous 1N HCl to pH 5-6 by litmus paper. The precipitate was filtered, washed with water, dried over Drierite to give the desired product (0.286 g, 0.533 mmol, 85% yield) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[C:8]([Cl:14])[C:3]=1[C:4]([O:6]C)=[O:5].[I-].[Li+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[C:8]([Cl:14])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(Cl)cc(CO)cc1Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(O)c1c(Cl)cc(CO)cc1Cl
Temperature: 25 °C
Yield: 72 %

Procedure:
A suspension of methyl 2,6-dichloro-4-(hydroxymethyl)benzoate (5.3 g, 22 mmol) in pyridine (20 mL) was treated with anhydrous lithium iodide (9 g, 67 mmol). The resulting reaction mixture was heated to reflux for 5 hours, cooled to room temperature and concentrated under vacuum. The residue was diluted with water and acidified with dilute hydrochloric acid (pH 2-3) and partitioned with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, concentrated and the residue obtained upon triturating with diethyl ether afforded 2,6-dichloro-4-(hydroxymethyl)benzoic acid as a pale yellow solid (3.5 g, 70%).
Reaction SMILES: O.NN.[CH2:4]([O:11][C:12]([CH:14]1[C:18]2([CH2:23][CH2:22][S:21][CH2:20][CH2:19]2)[S:17][CH:16]([CH:24]([N:32]2C(=O)C3=CC=CC=C3C2=O)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[NH:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:43]>CN(C)C=O>[ClH:43].[NH2:32][CH:24]([CH:16]1[NH:15][CH:14]([C:12]([O:11][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:13])[C:18]2([CH2:19][CH2:20][S:21][CH2:22][CH2:23]2)[S:17]1)[C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)C(C1NC(C(=O)OCc2ccccc2)C2(CCSCC2)S1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(N)C1NC(C(=O)OCc2ccccc2)C2(CCSCC2)S1
Reaction time: 1.25 h
Yield: 91.5 %

Procedure:
151.5 ml of a solution of dimethylforamide containing 2 moles per liter of hydrazine hydrate (0.3025 mole) are added, between 0 and 5° C, to a suspension of 156.3 g (0.275 mole) of tert-butyl 4-benzyloxycarbonyl-alpha-phthalimido-1,8-dithia-3-azaspiro[4.5]decane-2-acetate in 170 ml of anhydrous dimethylformamide. The addition is carried out over 75 minutes and is accompanied by a complete dissolution of the product. The reaction mixture is allowed to return to ambient temperature over a period of 1 hour, whereafter 309 ml of 1N hydrochloric acid are added dropwise at 20 to 25° C. The precipitate of phthaloghydrazide formed is filtered off and the mother liquors are evaporated to dryness. The residue is taken up in methanol and is precipitated with diethyl ether. In this way, there are obtained 119.1 g of tert-butyl alpha-amino-4-benzyloxycarbonyl-1,8-dithia-3-azaspiro[4.5]decane-2-acetate hydrochloride (yield 91.5% of theory); M.P. 178-181° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:22])[CH2:11][CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=[CH:8][CH:9]=1.Br[CH2:24][C:25]#[N:26].[NH4+].[Cl-]>CC#N.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([O:22][CH2:24][C:25]#[N:26])[CH2:11][CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH:7]=[CH:8][CH:9]=1
Reactant: CN(CCC(O)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Reactant: N#CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(CCC(OCC#N)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of NaH (0.65 g, 27 mmol) and tert-butyl 3-(3-chlorophenyl)-3-hydroxypropyl(methyl)carbamate (2.7 g, 9 mmol) in CH3CN (60 mL) at 0-5° C. was added drop wise a solution of bromoacetonitrile (3.3 g, 27 mmol) in CH3CN (20 mL), the reaction mixture was stirred for overnight at room temperature. The reaction mixture was poured into saturated aqueous NH4Cl, ethyl acetate (50 mL) was added. The organic layer was washed with water (3×20 mL) and brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the crude product, which was used for the next step without purification.
Reaction SMILES: C1(S(CC2C(C(OC)=O)=C(CCCNC(OC(C)(C)C)=O)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=CC=1.[C:37]1([S:43]([CH2:46][C:47]2[C:52]([C:53]([O:55][CH3:56])=[O:54])=[C:51]([NH:57]CC3C=CC=CC=3)[C:50]([C:65]3[CH:69]=[CH:68][O:67][CH:66]=3)=[CH:49][CH:48]=2)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[NH2:57][C:51]1[C:50]([C:65]2[CH:69]=[CH:68][O:67][CH:66]=2)=[CH:49][CH:48]=[C:47]([CH2:46][S:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:45])=[O:44])[C:52]=1[C:53]([O:55][CH3:56])=[O:54]
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1NCc1ccccc1
Agent: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1CCCNC(=O)OC(C)(C)C
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1N

Procedure:
Prepared by proceeding in a similar manner to Intermediate 131, starting from methyl 6-(benzenesulphonylmethyl)-2-benzylamino-3-(furan-3-yl)benzoate (Intermediate 213)
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH:7]([CH3:21])[CH:8]([NH:10]C(=O)OCC1C=CC=CC=1)[CH3:9])=[O:5]>CO.[Pd]>[NH2:10][CH:8]([CH3:9])[CH:7]([NH:6][C:4](=[O:5])[C:3]1[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=1[OH:1])[CH3:21]
Reactant: CC(NC(=O)OCc1ccccc1)C(C)NC(=O)c1ccccc1O
Agent: [Pd]
Solvent: CO
Product: CC(N)C(C)NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
A mixture of benzyl 3-(2-hydroxybenzamido)butan-2-ylcarbamate (3.2 g, 9.36 mmol) and 10% Pd/C (0.32 g) in MeOH (120 mL) was stirred under a H2 (1 atm) atmosphere (RT, 16 h). The mixture was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with MeOH-DCM (0-20%) to afford N-(3-aminobutan-2-yl)-2-hydroxybenzamide (1.67 g, 86%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][CH2:13]O)[O:7][CH2:6][CH2:5]2.Cl.[Br:16][C:17]1[CH:18]=[C:19]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.BrC1C=C(OC)C=CC=1N1CCNCC1.N1(C2C=CC(S(N)(=O)=O)=CC=2)CCNCC1>>[Br:16][C:17]1[CH:18]=[C:19]([S:29]([NH2:32])(=[O:30])=[O:31])[CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:13][CH2:12][C@H:8]2[C:9]3[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=3)[CH2:5][CH2:6][O:7]2)[CH2:25][CH2:24]1
Reactant: NS(=O)(=O)c1ccc(N2CCNCC2)c(Br)c1
Reactant: OCCC1OCCc2cc(Br)ccc21
Agent: COc1ccc(N2CCNCC2)c(Br)c1
Agent: Cl
Agent: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Product: NS(=O)(=O)c1ccc(N2CCN(CC[C@@H]3OCCc4cc(Br)ccc43)CC2)c(Br)c1

Procedure:
Following the general procedure of EXAMPLE 49 and making non-critical variations, 2-(6-bromoisochroman-1-yl)ethanol (LXXIX, 0.399 g) and 3-bromo-4-(piperazin-1-yl)- benzenesulfonamide hydrochloride (VIII, Chart C, 0.544 g; prepared by the method of EXAMPLE 37 but using 4-(piperazin-1-yl)benzenesulfonamide (IV) in place of 1-(4-methoxyphenyl)piperazine) are combined to give the title compound; mp 206-208°; MS (m/z) 557 and 559; IR (mineral oil) 1165, 1338, 1450, 616, 1586 and 731 cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:27][CH:24]([C:5]1[C:6]2[N:7]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]4[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=4)[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:25][CH3:26])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(Cl)cc1Cl
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(Cl)cc1Cl
Reaction time: 18 h
Yield: 94.3 %

Procedure:
To a stirred solution of 1-[10-chloro-1-(3,5-dichloropyridin-2-yl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-7-yl]propan-1-ol (200 mg, 0.470 mmol) in pyridine (1.0 mL) was added acetic anhydride (133 μL, 1.41 mmol) at room temperature. After 18 h, the reaction mixture was quenched with aqueous sodium hydrogen carbonate, diluted with ethyl acetate, washed with water, hydrochloric acid (1 M) and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (207 mg, 0.443 mmol, 94%). Analytically pure material was obtained by recrystallization from ethyl acetate/hexane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].ClC(=O)[C:31]([O:33]C)=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](=[O:21])[C:31]([OH:33])=[O:32]
Reactant: COC(=O)C(=O)Cl
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)C(=O)O)c(=O)n(C)c1=O

Procedure:
The title compound was synthesized following a similar procedure described in the synthesis of compound 2A from reaction of Example 1 with methyl 2-chloro-2-oxoacetate (hydrolysis of the crude upon column chromatography afforded Example 31). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.95 (s, 3H) 3.17 (s, 3H) 7.28 (s, 1H) 7.61 (m, 1H) 7.84 (m, 1H) [M+H] calc'd for C14H11FIN3O5, 448. found, 448.