Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].Cl>C(O)C>[C:1]([NH:4][C:5]([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCCCCCCCCCCCCCCCCCCCCCBr
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCCCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 57.8 %

Procedure:
Diethyl 2-acetamidomalonate (3.0 g) was dissolved in 50 ml of dry ethanol and 1.3 g of sodium ethoxide was added thereto. A solution of 6.5 g of docosyl bromide in 20 ml of dry ethanol was added thereto while stirring at room temperature. The inside of the reaction vessel was displaced with nitrogen and the mixture was refluxed for about 15 hours. The mixture was neutralized with a 1N aqueous hydrochloric acid solution and concentrated. The concentrate was purified by silica gel column chromatography to give 4.2 g of diethyl 2-acetamido-2-docosylmalonate.
Reaction SMILES: I[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:12](=O)([O-:14])[O-:13].[K+].[K+]>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:11][C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:12]([OH:14])=[O:13])[N:7]2[N:8]=1
Reactant: Cc1nc2cccc(I)n2n1
Reactant: O=C([O-])[O-]
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Product: Cc1nc2cccc(C(=O)O)n2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-iodo-2-methyl[1,2,4]triazolo[1,5-a]pyridine (13.5 g, 52.1 mmol) in methanol (521 mL) were added palladium acetate (1.17 g, 5.21 mmol), potassium carbonate (21.6 g, 156 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (2.15 g, 5.21 mmol), and the mixture was stirred under carbon monoxide atmosphere at 2 atm at room temperature for 1 hr. The mixture was warmed to 50° C. and stirred for 12 hr. The reaction mixture was filtered through celite. The solvent was evaporated under reduced pressure. The residue was dissolved in water (300 mL), washed with chloroform, and 2 M hydrochloric acid was added to adjust the solution to pH 2. The aqueous layer was evaporated under reduced pressure, the residue was dissolved in methanol, and insoluble material was filtered off. The solvent was evaporated under reduced pressure to give 2-methyl[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid as a crudely purified product.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:3]=1[C:23](O)=[O:24].Cl.Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:38][CH2:37][CH2:36][C@H:35]2[CH2:39][OH:40])[CH2:30][CH2:29]1>>[OH:40][CH2:39][C@@H:35]1[CH2:36][CH2:37][CH2:38][N:34]1[CH:31]1[CH2:32][CH2:33][N:28]([C:23]([C:3]2[C:4]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)=[N:5][N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=3)[C:2]=2[CH3:1])=[O:24])[CH2:29][CH2:30]1
Reactant: Cc1c(C(=O)O)c(-c2ccncc2)nn1-c1cccc(C(F)(F)F)c1
Reactant: OC[C@@H]1CCCN1C1CCNCC1
Agent: Cl
Product: Cc1c(C(=O)N2CCC(N3CCC[C@H]3CO)CC2)c(-c2ccncc2)nn1-c1cccc(C(F)(F)F)c1
Yield: 14 %

Procedure:
In analogy to the procedure described in Example 160E], 5-methyl-3-pyridin-4-yl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid (Example 160D]) and ((S)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanoldihydrochloride (Example 161A]) gave the title compound as a light yellow oil (14%). MS: 514.0 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C@H:13]([OH:14])[CH2:12][CH2:11][N:10]([C:15]([C:17]2[CH:39]=[CH:38][C:20]3[N:21]([CH3:37])[C:22]([C:24]4[N:32]([CH2:33][CH:34]5[CH2:36][CH2:35]5)[C:27]5=[N:28][CH:29]=[CH:30][CH:31]=[C:26]5[CH:25]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.CO>[NH2:7][C@@H:8]1[C@H:13]([OH:14])[CH2:12][CH2:11][N:10]([C:15]([C:17]2[CH:39]=[CH:38][C:20]3[N:21]([CH3:37])[C:22]([C:24]4[N:32]([CH2:33][CH:34]5[CH2:36][CH2:35]5)[C:27]5=[N:28][CH:29]=[CH:30][CH:31]=[C:26]5[CH:25]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1
Reactant: Cn1c(-c2cc3cccnc3n2CC2CC2)nc2cc(C(=O)N3CC[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C3)ccc21
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(-c2cc3cccnc3n2CC2CC2)nc2cc(C(=O)N3CC[C@@H](O)[C@@H](N)C3)ccc21
Reaction time: 1 h
Yield: 100 %

Procedure:
To a flask containing tert-butyl((3S,4R)-1-(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl)-4-hydroxypiperidin-3-yl)carbamate (37 mg, 0.068 mmol) in dichloromethane (DCM) (1 mL) was added TFA (0.199 mL, 2.58 mmol) and the reaction was stirred for 1 h. The reaction mixture was concentrated in vacuo to afford a brown oil. This was dissolved in methanol and loaded onto an SCX cartridge (5 g). It was eluted with methanol (3 column volumes) and product eluted as free base with 2M ammonia in methanol. The filtrate from the ammonia fractions was concentrated in vacuo to yield a yellow oil—((3S,4R)-3-amino-4-hydroxypiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone (32 mg, 0.068 mmol, 100% yield). This was dissolved in dichloromethane (DCM) (1 mL) in a vial and HCl (2 M in Et2O) (0.034 mL, 0.068 mmol) was added. The resultant suspension was sonicated for 5 min and allowed to stand for 15 min. The solvent was then removed under a positive pressure of nitrogen and the product dried in vacuo to afford ((3S,4R)-3-amino-4-hydroxypiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride (32 mg, 0.067 mmol, 98% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[C:7]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:9])[CH3:8]>>[C:11]1([N:10]([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)[C:7](=[O:9])[CH3:8])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: Brc1ccsc1
Product: CC(=O)N(c1ccccc1)c1ccsc1
Yield: 82 %

Procedure:
Using general procedure C, 3-bromothiophene was coupled with acetanilide with the reaction time of 15 h. Chromatography gave 178 mg (82%) of the title compound as an oil. 1H NMR (CDCl3, 300 MHz): δ 7.44 (br s, 3H), 7.28 (s, 2H), 7.18 (s, 2H), 6.94 (d, 1H, J=4.8 Hz), 1.99 (br s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[CH:26]=[CH:27][CH:28]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)O)=[CH:13][CH:12]=[CH:11][C:10]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C.[PH2](O)=O>[CH2:1]([O:8][C:9]1[C:14]([CH:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])[CH:26]=[CH:27][CH:28]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1-c1cccc(C(O)(c2ccccc2)c2cccc(-c3ccccc3)c2OCc2ccccc2)c1
Agent: O=[PH2]O
Solvent: CC#N
Product: COc1ccccc1-c1cccc(C(c2ccccc2)c2cccc(-c3ccccc3)c2OCc2ccccc2)c1
Yield: 50.9 %

Procedure:
A solution of 26 (0.85 g, 1.55 mmol) in acetonitrile (50 mL) and 50% aqueous hypophosphorous acid (21 mL) was kept at reflux for 3.5 hr. The acetonitrile was removed in vacuo, the residue was diluted with ethyl acetate (150 mL) and water (80 mL). Phases were separated. The organic phase was washed with saturated sodium bicarbonate (2×80 mL) and water (2×80 mL) dried over sodium sulfate and filtered. The solvent was removed on a rotary evaporator. The crude product was purified by chromatography on silica (45 g) with 2% ethyl acetate in heptane (4 L) to yield pure D2 (0.42 g, 69%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.Cl.[NH2:23][C@H:24]([CH3:29])[C:25]([CH3:28])([OH:27])[CH3:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:27][C:25]([CH3:28])([CH3:26])[C@H:24]([NH:23][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=2)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1)=[O:13])[CH3:29]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Reactant: C[C@@H](N)C(C)(C)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
In a flask were combined 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3.25 g, 8.74 mmol), (R)-3-amino-2-methyl-butan-2-ol hydrochloride (3.05 g, 21.9 mmol), EDC (3.85 g, 20.1 mmol) and HOBt (2.72 g, 20.1 mmol). Then added DMF (50 mL) followed by i-Pr2NEt (4.87 mL, 28.0 mmol). The mixture was stirred at room temperature overnight then concentrated under reduced pressure. The residue purified by SiO2 chromatography (20-100% EtOAc/hexane) to afford 2.40 g (60%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1,2-dimethyl-propyl)-amide as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].C(N(CC)CC)C.F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]1[C:36]([C:37]([OH:39])=[O:38])=[C:35]2[C:30]([C@H:31]3[CH2:42][CH2:41][O:40][C@H:32]3[CH2:33][O:34]2)=[CH:29][CH:28]=1)(=[O:25])=[O:24]>C(#N)C.O>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]1[C:36]([C:37]([OH:39])=[O:38])=[C:35]2[C:30]([C@H:31]3[CH2:42][CH2:41][O:40][C@H:32]3[CH2:33][O:34]2)=[CH:29][CH:28]=1)(=[O:25])=[O:24]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OC[C@@H]1OCC[C@H]21
Reactant: CN(C)CCCCN
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)CCCCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OC[C@@H]1OCC[C@H]21
Temperature: 130 °C
Yield: 33.2 %

Procedure:
4-Dimethylaminobutylamine (0.348 g) and triethylamine (0.2 ml) were added to a suspension of cis-(3aRS,9bRS)-7-(2-fluorobenzenesulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid (Intermediate 57, 0.15 g) in acetonitrile (1.5 mL) and the mixture was heated at 130° C. in a sealed tube for 36 hours. The mixture was then diluted with water (2 mL) and the solution was purified by preparative HPLC (C6-phenyl) eluting with a mixture of methanol and water, containing 0.1% formic acid, with a gradient of 5-98%. The isolated product was further purified by chromatography on silica eluting with a mixture of methanol and DCM with a gradient of 0-15% to give cis-(3aRS,9bRS)-7-[2-(4-dimethylaminobutylamino)-benzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid (0.062 g) as a glass foam.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:33][C:34]1[C:35]([F:44])=[C:36]2[C:42]([NH2:43])=[CH:41][NH:40][C:37]2=[N:38][CH:39]=1.[Li+].[OH-].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:33][C:34]1[C:35]([F:44])=[C:36]2[C:42]([NH:43][C:7](=[O:9])[C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)=[CH:41][NH:40][C:37]2=[N:38][CH:39]=1
Reactant: Cc1cncc(C(=O)O)c1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cncc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
5-Methylnicotinic acid (477 mg, 3.48 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (885 mg, 3.48 mmol) and triethylamine (880 mg, 8.69 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (400 mg, 1.74 mmol) in DCM (200 mL). The reaction was stirred at room temperature for 1 hour, and then 3M aqueous LiOH (4 mL) was added. The reaction was stirred for 1 hour, and then saturated aqueous Na2CO3 was added (200 mL). The aqueous phase was extracted once with DCM (200 mL), and then the aqueous phase was filtered. The filtered cake was dried to yield N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylnicotinamide (228 mg, 37.6% yield) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.F[C:14]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:15]=1[CH:16]=[O:17].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH:16]([C:15]1[CH:18]=[C:19]([C:22]([F:23])([F:24])[F:25])[CH:20]=[CH:21][C:14]=1[O:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[O:17]
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: CC(C(=O)O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C(=O)O)c1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
2-(3-Hydroxy-phenyl)-propionic acid (0.1 g, 0.60 mmol), 2-fluoro-5-(trifluoromethyl)benzaldehyde (0.115 g, 0.60 mmol), and potassium carbonate (0.165 g, 1.19 mmol) were combined in THF and stirred at 70° C. overnight. The mixture was partitioned between H2O and EtOAc and acidified with 1N aqueous HCl to pH 1, and then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and residue was purified by silica gel chromatography to give the desired product.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([OH:17])=[O:16])[CH:8]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O.CO>[CH2:24]([O:1][C:2]1[C:11]([C:12]([O:14][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([O:17][CH2:5][C:4]3[CH:9]=[CH:10][CH:11]=[CH:2][CH:3]=3)=[O:16])[CH:8]=2)[CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc2cc(O)c(C(=O)O)cc2c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc2cc(OCc3ccccc3)c(C(=O)OCc3ccccc3)cc2c1
Temperature: 100 °C
Yield: 134.8 %

Procedure:
2-Hydroxy-3,6-di-hydroxycarbonylnaphthalene (2.4 g) was dissolved in dimethylformamide (50 g), followed by heating to 100° C. Potassium carbonate (4.6 g) was slowly added and benzyl chloride (4.2 g) was added dropwise. After heating for about 20 hours, the reaction solution was poured into a mixed solution of water (300 g) and methanol (100 g). The deposit was filtered and then washed with water to obtain 3.5 g of 2-benzyloxy-3,6-di-benzyloxycarbonylnaphthalene as whitish yellow powder (DSC analysis value: 100.5° C.).
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:8]=[C:9]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15].[C:21](Cl)(Cl)=[S:22]>O.C(Cl)(Cl)Cl>[CH:14]([O:13][C:12]1[CH:11]=[CH:10][C:9]([S:17]([NH2:20])(=[O:18])=[O:19])=[CH:8][C:7]=1[N:6]=[C:21]=[S:22])([CH3:16])[CH3:15]
Reactant: S=C(Cl)Cl
Reactant: CC(C)Oc1ccc(S(N)(=O)=O)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccc(S(N)(=O)=O)cc1N=C=S
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of sodium bicarbonate (16.8 g, 199.5 mmol) in water (400 mL) was added to 3-amino-4-isopropoxy-benzenesulfonamide (15.3 g, 66.5 mmol, example 2, step d) in a mixture of chloroform (200 mL) and water (200 mL). Thiophosgene (6.37 mL, 83.1 mmol) was then added. The biphasic solution was stirred at room temperature for 1.5 h. The phases were separated and the aqueous phase was extracted with CH2Cl2. The organic phase was washed with water, dried (Na2SO4), filtered, and concentrated, yielding the crude title compound as a tan solid.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=1.[OH-].[Li+].O>CO>[I:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:10][CH:11]=1
Reactant: COC(=O)Cc1ccc(CCCCI)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1ccc(CCCCI)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.9 %

Procedure:
Methyl 4-(4-iodo-1-butyl)phenylacetate (21.28 g, 0.064 mol) was dissolved in methanol (160 mL). Lithium hydroxide (6.72 g, 0.16 mol) and water (10 mL) were added, and the reaction mixture was stirred for 18 hours at room temperature. The solvents were removed under reduced pressure, the residue was treated with ethyl acetate (600 mL), and the organic solution was washed with 1N HCl (3×300 mL), brine (3×300 mL), dried over MgSO4, and filtered. The filtrate was concentrated and dried in vacuo to give 17.5 g (85.9 %) of 4-(4-iodo-1-butyl)phenylacetic acid as a yellow solid. 1H NMR (300 MHz, CD3OD) δ: 1.68-1.84 (m, 4H), 2.61 (t, 2H, J=7.35 Hz), 3.24 (t, 2H, J=6.75 Hz), 3.55 (s, 2H), 7.16 (ab quartet, 4H, J=8.26 Hz). FAB-MS m/z=319 (M+H); HRMS calcd for C12H16O2I (M+H) 319.0194, found 319.0208.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:9][NH2:10]>C1COCC1>[Br:1][C:2]1[C:3]([NH:9][NH2:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccc1Br
Reactant: NN
Solvent: C1CCOC1
Product: NNc1ncccc1Br
Reaction time: 16 h

Procedure:
To 3-bromo-2-chloropyridine (1-3) (12.5 g, 65 mmol) in THF (100 mL) was added hydrazine (10.4 g, 10.2 mL, 325 mmol). The mixture was heated to reflux and stirred vigorously for 16 h. An additional portion of hydrazine (5.1 g, 5.0 mL, 159 mmol) was added and the reaction was heated for another 24 h. After cooling, the mixture was concentrated in vacuo, suspended in water (50 mL), and extracted with EtOAc (1×350 mL, 1×50 mL). Combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude product (1-4) was used in the subsequent step without further purification. LC/MS: m/z (M+H)=187.9.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[C:8]([CH3:19])=[N:9][C:10]2[N:11]([N:13]=[C:14]([CH2:16][O:17][CH3:18])[N:15]=2)[CH:12]=1>CN(C)C1C=CC=CC=1>[Cl:3][C:12]1[N:11]2[N:13]=[C:14]([CH2:16][O:17][CH3:18])[N:15]=[C:10]2[N:9]=[C:8]([CH3:19])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1nc2nc(C)c(O)cn2n1
Solvent: CN(C)c1ccccc1
Product: COCc1nc2nc(C)cc(Cl)n2n1
Reaction time: 1 h

Procedure:
To a mixed solution of 300 ml of phosphorus oxychloride and 50 ml of N,N-dimethylaniline was added 38.8 g of -hydroxy-2-methoxymethyl-5-methyl-s-triazolo[1,5-a]-pyrimidine, and the mixture was stirred at 50° to 60 ° C. for one hour. After removing phosphorus oxychloride, the residue was dissolved in 500 ml of chloroform and stirred by adding ice. The chloroform layer was separated and washed with water, and then dried over anhydrous magnesium sulfate and distilled the solvent to obtain crystals. The crystals were collected by filtration and washed with water, and then dried to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:12][CH3:13])[CH2:10][OH:11])[C:5]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S@@:26]([CH:34]2[CH2:36][CH2:35]2)(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])=[CH:22][CH:21]=1>>[CH2:32]([O:31][C:29]([N:28]=[S@@:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:2]2[N:7]=[C:6]([NH:8][C@@H:9]([CH2:10][OH:11])[CH2:12][CH3:13])[C:5]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:4][N:3]=2)=[CH:25][CH:24]=1)([CH:34]1[CH2:35][CH2:36]1)=[O:27])=[O:30])[CH3:33]
Reactant: CCOC(=O)N=[S@@](=O)(c1ccc(N)cc1)C1CC1
Reactant: CC[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: CCOC(=O)N=[S@@](=O)(c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](CC)CO)n2)cc1)C1CC1
Yield: 47 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)butan-1-ol (300 mg, 1.06 mmol) with (S)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-cyclo-propyl-sulfoximide (258 mg, 0.96 mmol) according to procedure 5c, the desired product is obtained in 47% yield (256 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: N1CCCCC1.[CH2:7]([C@@H:14]1[CH2:19][C@@H:18]([N:20]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[CH:30][CH:29]=2)[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:17][CH2:16][N:15]1[C:38]([C@H:40]1[N:52](C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:51][C:43]2[NH:44][C:45]3[C:50]([C:42]=2[CH2:41]1)=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:39])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)C=O>[CH2:7]([C@@H:14]1[CH2:19][C@@H:18]([N:20]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=[CH:30][CH:29]=2)[C:21](=[O:26])[C:22]([F:25])([F:23])[F:24])[CH2:17][CH2:16][N:15]1[C:38]([C@H:40]1[NH:52][CH2:51][C:43]2[NH:44][C:45]3[C:50]([C:42]=2[CH2:41]1)=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:39])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C([C@@H]1Cc2c([nH]c3ccccc23)CN1C(=O)OCC1c2ccccc2-c2ccccc21)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: O=C([C@@H]1Cc2c([nH]c3ccccc23)CN1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.97 ml, 19.9 mmol) of piperidine are added to a solution of 338 mg (0.399 mmol) of (2R*,4S*)-2-benzyl-1-((3S)-(2-(9-fluorenylmethyloxycarbonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-yl)carbonyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine in 3 ml of N,N-dimethylformamide, and the mixture is stirred at room temperature for 2 hours. It is then concentrated in a rotary evaporator, and the residue is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (2000:50:1) to separate the diastereomers. TLC: methylene chloride/methanol/conc. ammonia (700:50:1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13](I)[N:14]=[C:7]3[C:6]=2[CH:16]=1.C([Mg]Br)C.[NH4+].[Cl-]>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[CH:13][N:14]=[C:7]3[C:6]=2[CH:16]=1
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)-c1nccn1CCO2
Temperature: 25 °C

Procedure:
To a solution of 10-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (9 g, 20 mmol) in THF (40 mL) was added Ethylmagnesium bromide in Ethyl ether (22 mL) at −20° C. The mixture was allowed to warm to room temperature and in one and half hour the completion was showed by LCMS. The reaction mixture was poured into 10% NH4Cl and extracted by EtOAc. Organic layer was washed by brine, dried by MgSO4 and concentrated. The crude was purified by Isco chromatography to afford 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine. LC/MS (ESI+): m/z 265 (M+H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C(OC([N:19]1[CH2:24][CH2:23][C:22]2([CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]2)[CH2:21][CH2:20]1)=O)(C)(C)C>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH:27]1[CH2:28][CH2:29][C:22]2([CH2:23][CH2:24][NH:19][CH2:20][CH2:21]2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Reactant: Oc1ccc2ccccc2c1
Product: c1ccc2cc(OC3CCC4(CCNCC4)CC3)ccc2c1

Procedure:
Was prepared according to method A from 2-naphthol and 9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester. Mp. 132.2-133.8° C.