Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH:13]C(OC(C)(C)C)=O)[C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]1=2.P(=O)(O)(O)O.[OH-].[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH2:13])[C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]1=2
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)c2ccccc2-c2ccccc21
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)CN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21

Procedure:
((S)-7-tert-Butoxycarbonylamino-6-oxo-6,7-dihydro-dibenzo[b,d]azepin-5-yl)-acetic acid methyl ester (60 mg, 0.15 mmol) were dissolved in dichloromethane (3 ml), treated with 0.15 ml (2.3 mmol) orthophosphoric acid and stirred for 18 .h The reaction mixture is adjusted to pH 7.5 with 2N aqueous sodium hydroxide, diluted with dichloromethane (5 ml) and the phases separated. After extraction of the organic phases with water (5 ml) and saturated aqueous sodium chloride (5 ml), the solution is dried with magnesium sulfate and evaporated to dryness. White solid (60%); MS: m/e=297(M+H+), which was used without further purification.
Reaction SMILES: ClC(OCC)=O.Br.[CH3:8][CH:9]1[CH2:20][C:19]2[NH:18][CH:17]=[C:16]([C:21]([OH:23])=O)[C:15]=2[C:14]2[N:10]1[CH:11]=[CH:12][N:13]=2.[F:24][C:25]1[CH:31]=[C:30]([O:32][CH:33]([CH3:35])[CH3:34])[CH:29]=[CH:28][C:26]=1[NH2:27].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O.C(O)C.CN(C)C=O.C(N(CC)CC)C>[F:24][C:25]1[CH:31]=[C:30]([O:32][CH:33]([CH3:34])[CH3:35])[CH:29]=[CH:28][C:26]=1[NH:27][C:21]([C:16]1[C:15]2[C:14]3[N:10]([CH:11]=[CH:12][N:13]=3)[CH:9]([CH3:8])[CH2:20][C:19]=2[NH:18][CH:17]=1)=[O:23]
Reactant: CC(C)Oc1ccc(N)c(F)c1
Reactant: CC1Cc2[nH]cc(C(=O)O)c2-c2nccn21
Agent: Br
Agent: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(NC(=O)c2c[nH]c3c2-c2nccn2C(C)C3)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl chloroformate (66 μL) is added dropwise to an ice-cold mixture of 4-methyl-5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid hydrobromide (192 mg), triethylamine (0.33 mL), and N,N-dimethylformamide (5 mL). The mixture is stirred at 0° for 1 hour then at room temperature for 30 minutes. 2-Fluoro-4-isopropoxyaniline (66 mg) is added and the mixture is stirred at room temperature for 18 hours. The mixture is diluted with ethyl acetate (50 mL) then treated with water (25 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers are washed with water (2×20 mL) and brine (1×20 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by preparative thin layer chromatography on silica gel, eluting with diethyl ether, to give a brown solid. This is treated with ethanol (2 mL) and saturated aqueous potassium carbonate solution (1 mL) and the mixture is heated at 60° for 30 minutes. The mixture is cooled to room temperature and diluted with water (3 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers are washed with brine (1×10 mL), dried over magnesium sulfate, and concentrated in vacuo. The oily residue is purified by preparative thin layer chromatography on silica gel, eluting with 10% methanol in dichloromethane, to give 4-methyl-5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid (2-fluoro-4-isopropoxyphenyl)amide, pale yellow solid, 10 mg: LRMS calcd 368.40, found [M+H] 369.2.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[C:10]([CH2:21][NH:22][CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([NH:31][C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:9][C:10]=2[CH2:21][NH:22][CH3:23])[CH2:15][CH2:16]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1C1CCC(=O)CC1
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NCc2ccccc2)CC1

Procedure:
from 4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-cyclohexanone and benzylamine. Colourless oil. Rf value: 0.45 (alumina, petroleum ether/ethyl acetate=2:1, v:v).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C@H:3]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[N:16]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][C:20](Br)=[C:19]([CH3:27])[CH:18]=3)=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:4].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:36]1.C([O-])(=O)C.[K+]>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]([F:34])([F:33])[C@H:3]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[N:16]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][C:20]([OH:36])=[C:19]([CH3:27])[CH:18]=3)=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:4]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Cc1cc2c(cc1Br)c(C#N)c(-c1ccc(S(=O)(=O)N[C@H](C)C(F)(F)F)cn1)n2C1CCCC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc2c(cc1O)c(C#N)c(-c1ccc(S(=O)(=O)N[C@H](C)C(F)(F)F)cn1)n2C1CCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
A mixture of (R)-6-(5-bromo-3-cyano-1-cyclopentyl-6-methyl-1H-indol-2-yl)-pyridine-3-sulfonic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide (0.54 g, 0.97 mmol), bis(pinacolato)diboron (0.5 g, 2.0 mmol), PdCl2dppf-CH2Cl2 complex (16 mg, 0.02 mmol) and potassium acetate (0.40 g, 4.0 mmol) in dioxane (5 mL) was stirred at 80° C. overnight. The mixture was then cooled to room temperature, diluted with ethyl acetate and filtered through a silica-celite pad. The filtrate was concentrated, dissolved in acetone (10 mL) and cooled to 0° C. Into this solution was added an aqueous solution of Oxone (10 mL, 1.0 M). The mixture was stirred at room temperature for 15 min and diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organic extractions were combined and washed with aq. NaHSO3 and brine, dried over Na2SO4, and concentrated. Purification on silica gel eluting with 40% ethyl acetate in hexane gave (R)-6-(3-cyano-1-cyclopentyl-5-hydroxy-6-methyl-1H-indol-2-yl)-pyridine-3-sulfonic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide as a yellow solid (0.40 g, 84%); Melting point: 239-240° C.; MS m/z 493.2 M+H+; 1H NMR (500 MHz, CD3COCD3) δ 9.24 (dd, J=2.30, 0.65 Hz, 1H), 8.50 (dd, J=8.25, 2.35 Hz, 1H), 8.42 (s, 1H), 8.10 (dd, J=8.25, 0.85 Hz, 1H), 7.47 (bs, 1H), 7.54 (s, 1H), 7.15 (s, 1H), 5.30-5.26 (m, 1H), 4.40-4.35 (m, 1H), 2.40 (s, 3H), 2.34-2.31 (m, 2H), 2.16-2.14 (m, 2H), 2.10-2.07 (m, 2H), 1.74-1.72 (m, 2H), 1.21 (d, J=2.25 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[O:12][CH2:13][CH2:14][O:15][C:5]=3[C:4]=2[N:3]1[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]1.Cl>C(Cl)(Cl)Cl.O1CCOCC1.CO>[NH2:24][CH:21]1[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][N:3]2[C:4]3[C:5]4[O:15][CH2:14][CH2:13][O:12][C:6]=4[CH:7]=[CH:8][C:9]=3[CH:10]=[CH:11][C:2]2=[O:1])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc4c(c32)OCCO4)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: NC1CCN(CCn2c(=O)ccc3ccc4c(c32)OCCO4)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
1,1-dimethylethyl {1-[2-(9-oxo-2,3-dihydro[1,4]dioxino[2,3-h]quinolin-10(9H)-yl)ethyl]-4-piperidinyl}carbamate (1 g; 2.34 mmol) was dissolved in chloroform (8 ml) and 4M HCl in 1,4-dioxane (10 ml) added. This was then stirred at rt for 1 h. The salts from the reaction were dissolved in MeOH and all solvents then removed. The residues were redissolved in MeOH and stirred with amberlyst ion exchange resin until a neutral pH was reached. The resin was filtered off and all solvents were removed. The crude residues were subjected to column chromatography on silica gel using a 0-20% 2M NH3: MeOH/DCM gradient to give the desired product (425 mg; 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[CH2:19]([Li])CCC.IC>C1COCC1.O.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])=[C:4]([CH3:19])[C:3]=1[C:15]([F:16])([F:17])[F:18]
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(NC(=O)C(C)(C)C)ccc(Cl)c1C(F)(F)F
Reaction time: 1.5 h
Yield: 67 %

Procedure:
To a solution of N-(4-chloro-3-trifluoromethylphenyl)-2,2-dimethylpropionamide (2.29 g, 8.19 mmol) in anhydrous THF (25 mL) cooled to 0–5° C. was added a solution of 1.6 M n-butyllithium in hexanes (12.3 mL, 19.7 mmol), added slowly so that the reaction temperature was maintained below 5° C. The solution was stirred at 0–5° C. for 1.5 h. A solution of iodomethane (0.56 mL, 9.01 mmol) in petroleum ether (2 mL) was added over 20 min while maintaining the temperature below 5° C. The suspension was stirred at 0–5° C. for 1 h and diluted with water and ether. The aqueous layer was extracted with ether and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chomatographed (silica gel), eluting with CH2Cl2 to afford compound 841B (1.60 g, 67%). MS (ES): m/z=294 [M+1]+.
Reaction SMILES: [C:1](=[O:3])=[O:2].[NH:4]([CH:6]([OH:8])[CH3:7])[NH2:5].O>>[C:1](=[O:8])([OH:3])[OH:2].[NH:4]([CH:6]([OH:8])[CH3:7])[NH2:5]
Reactant: O=C=O
Agent: CC(O)NN
Solvent: O
Product: O=C(O)O

Procedure:
Carbon dioxide was introduced until saturation into a mixture of 500 g of hydrazinoethanol (6.58 mol) and 59 g of water (3.29 mol). 49.5 l of carbon dioxide (2.2 mol) were absorbed while the temperature rose to 83° C.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([I:12])[C:3]=1[NH2:4].[N-:13]=[N+:14]=[N-].[Na+]>S(=O)(=O)(O)O.O>[I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([I:12])[C:3]=1[N:4]=[N+:13]=[N-:14]
Reactant: Nc1c(I)cc([N+](=O)[O-])cc1I
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1c(I)cc([N+](=O)[O-])cc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5 g of 2,6-diiodo-4-nitroaniline was dissolved in 20 ml of conc. sulfuric acid and cooled with ice. Sodium nitrite previously vacuum-dried was added to the solution in portions to effect the diazotization reaction at 0°-5° C. The reaction product was added dropwise to ice-water to dilute the sulfuric acid. A solution of 1.4 g of sodium azide in 10 cc of water was added dropwise to the mixture, stirred for about one hour, filtered and washed with water. After the recrystallization from ethanol followed by drying, 2,6-diiodo-4-nitroazidobenzene was obtained.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][OH:10]>C(O)C>[OH:10][NH:9][C:1](=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccccc1
Solvent: CCO
Product: N=C(NO)c1ccccc1
Yield: 68.9 %

Procedure:
Benzonitrile (5 g, 48 mmol) was dissolved in ethanol (100 ml) and treated with 50% aqueous hydroxylamine (16 ml, 242 mmol). Reaction was heated to reflux for 3 hours before concentration under reduced pressure to give a clear foam (4.5 g, 68%).
Reaction SMILES: [C:1]([O:15][C@H:16]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[C:28]([NH:36][C:37](=[O:53])[CH2:38][CH:39]2[C:52]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[O:46][C:45]3[C:40]2=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:27]=1)[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)(=[O:14])[CH2:2][CH2:3][C:4]([O:6]CC1C=CC=CC=1)=[O:5].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:15][C@H:16]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:33])([CH3:34])[CH3:35])=[C:28]([NH:36][C:37](=[O:53])[CH2:38][CH:39]2[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:45]=3[O:46][C:47]3[C:52]2=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:27]=1)[CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)(=[O:14])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)c1ccc(CC[C@H](CC2CCCCC2)OC(=O)CCC(=O)OCc2ccccc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(CC[C@H](CC2CCCCC2)OC(=O)CCC(=O)O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
A solution of 337 mg (0.471 mmol) of (R)-1-(2-{4-t-butyl-3-[2-(9H-xanthen-9-yl)acetamido]phenyl}ethyl)-2-cyclohexylethyl benzyl succinate (prepared as described in Preparation 25) in 10 ml of ethyl acetate was vigorously stirred in a stream of hydrogen in the presence of 173 mg of 10% w/w palladium-on-charcoal. The reaction mixture was then filtered, and the catalyst was washed with ethyl acetate. The filtrate and the washings were combined, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through 15 g of silica gel, using a 1:19 by volume mixture of methanol and methylene chloride as the eluent, to give the title compound as a foam-like material.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(C)c(F)cc1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)c(F)cc1-c1cccc-3c1
Yield: 94 %

Procedure:
Prepared in 94% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,18,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. 1H NMR (500 MHz, CDCl3) δ 8.20 (dt, J=7.9, 1.4 Hz, 1H), 8.15 (t, J=1.5 Hz, 1H), 8.03 (s, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.33 (s, 1H), 7.30 (dt, J=7.8, 1.3 Hz, 1H), 7.10-7.05 (m, 1H), 6.81 (d, J=6.5 Hz, 1H), 6.06 (br. s., 1H), 4.49 (td, J=6.3, 3.1 Hz, 1H), 3.97 (t, J=10.7 Hz, 1H), 3.81-3.77 (m, 1H), 3.76 (s, 3H), 3.57-3.47 (m, 2H), 3.15-3.08 (m, 1H), 2.71 (d, J=7.6 Hz, 1H), 2.47 (d, J=0.8 Hz, 3H), 2.34 (d, J=1.4 Hz, 3H), 2.00-1.69 (m, 10H), 1.30 (s, 3H), 1.26 (s, 9H), 1.12 (d, J=6.1 Hz, 3H); LCMS (ESI, M+1): 672.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=1.C([Li])CCC.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)([OH:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC1(C)COC(c2cc(Cl)ccc2Br)=N1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)COC(c2cc(Cl)ccc2C2(O)CCN(C(=O)OC(C)(C)C)CC2)=N1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a cold (−78° C.) solution of the product of step 1 (1.09 g, 4.63 mmol) in anhydrous tetrahydrofuran (10 mL) was added a solution of n-butyllithium (1.6 M in hexanes, 2.89 mL, 4.63 mmol) and the contents of the reaction were allowed to react for 0.5 h. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (922 mg, 4.63 mmol) in tetrahydrofuran (10 mL) was added and the combined contents stirred for 2 h at −78° C. Reaction was quenched by the addition of saturated aqueous ammonium chloride (30 mL), followed by warming to rt. The biphasic mixture was extracted with ethyl acetate (150 mL); washed with water and brine; dried over magnesium sulfate; filtered and concentrated. 4-[4-Chloro-2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-phenyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester was isolated (412 mg, 22%) following silica gel chromatography (80% hexanes/20% ethyl acetate).
Reaction SMILES: [OH:1][C@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Li+].CC([N-]C(C)C)C.C([Li])CCC.C(NC(C)C)(C)C.[C:29]1([CH:35]2[CH2:40][CH2:39][CH:38]([CH2:41]I)[CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[OH:1][C@H:2]([CH3:8])[C@@H:3]([CH2:41][CH:38]1[CH2:37][CH2:36][CH:35]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:40][CH2:39]1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: ICC1CCC(c2ccccc2)CC1
Reactant: COC(=O)C[C@@H](C)O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)[C@H](CC1CCC(c2ccccc2)CC1)[C@@H](C)O
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
A solution of methyl (3R)-3-hydroxybutyrate (5.6 g, 0.047 mol) in THF (20 mL) is added dropwise to a solution of LDA prepared by dropwise addition of n-butyllithium (49.5 mL, 0.099 mol, 2 M in cyclohexane) to diisopropylamine (10.0 g, 0.099 mol) in THF (20 mL) at −78° C. After stirring at −50° C. to −40° C. for 0.5 h, a solution of 4-phenylcyclohexylmethyl iodide (14.6 g, 0.049 mol) in a mixture of HMPA (10 mL) and THF (15 mL) is added dropwise. The mixture is kept at −20° C. for 48 h, then allowed to warm to 4 ° C. and kept at that temperature for 48 h. The reaction mixture is chilled to 0° C. and quenched by dropwise addition of saturated aqueous ammonium chloride solution. The aqueous phase is extracted with ether and the combined organic phase is washed with ice-cold 0.1 M HCl, then saturated sodium chloride solution and dried over sodium sulfate. Concentration of the organic phase gives 14.6 g of crude product. Column chromatography on silica gel with hexanes-EtOAc (2:1) as eluent affords 4.18 g (31%) of methyl (2R,3R)-3-hydroxy-2-(4-phenylcyclohexylmethyl)butanoate as a pale yellow oil which solidified on standing.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:12]Cl.[CH3:14][S:15]([O-:17])=[O:16].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:12][S:15]([CH3:14])(=[O:17])=[O:16]
Reactant: CS(=O)[O-]
Reactant: ClCc1cnc2ccccc2c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-Chloro-3-chloromethylquinoline (14.2 g.) was added to a stirred suspension of sodium methanesulphinate (7.3 g.) in dimethylformamide (150 ml.) at room temperature. The mixture was stirred for 14 hours at room temperature, then for 0.5 hour at 95°-100°. The solvent was evaporated to half volume and water added to the residue. The resulting solid product was collected and dissolved in dichloromethane. The solution was dried, filtered from charcoal, and evaporated. The resulting solid was triturated with petroleum ether to give the novel compound 4-chloro-3-methylsulphonylmethylquinoline, m.p. 202°-204°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([NH:31]C(=O)OC(C)(C)C)[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20]4[CH:27]([CH3:28])[S:26](=[O:30])(=[O:29])[CH2:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1>C(Cl)Cl.CO>[NH2:31][C@H:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:20]3[CH:27]([CH3:28])[S:26](=[O:30])(=[O:29])[CH2:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:15][CH2:14]1)=[O:12]
Reactant: CC1c2c(ncnc2N2CCN(C(=O)[C@@H](Cc3ccc(Cl)cc3)NC(=O)OC(C)(C)C)CC2)CS1(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC1c2c(ncnc2N2CCN(C(=O)[C@H](N)Cc3ccc(Cl)cc3)CC2)CS1(=O)=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
HCl (4M, 1 mL) was added to a solution of (2R)-tert-butyl 3-(4-chlorophenyl)-1-(4-(5-methyl-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (0.10 g, 0.18 mmol) in DCM (5 mL) and MeOH (1 mL). The mixture was stirred at room temperature for 6 hours. The solvent was removed to afford (2R)-2-amino-3-(4-chlorophenyl)-1-(4-(5-methyl-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one as the di-hydrochloride salt. LCMS: 450.1 [M+H+] (APCI+).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:25])[N:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=O)[S:14][CH:15]=3)[C:5]=2[NH:4][N:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C>[NH2:1][C:2]1[C:6]2[C:7](=[O:25])[N:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH2:16][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[S:14][CH:15]=3)[C:5]=2[NH:4][N:3]=1
Reactant: Nc1n[nH]c2c(-c3csc(C=O)c3)cn(-c3ccccc3Cl)c(=O)c12
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Nc1n[nH]c2c(-c3csc(CN4CCCC4)c3)cn(-c3ccccc3Cl)c(=O)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(3-amino-5-(2-chlorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-7-yl)thiophene-2-carbaldehyde obtained in Step A (100 mg) and pyrrolidine (0.053 mL) in acetonitrile (10 mL) was added sodium triacetoxyborohydride (89 mg) at room temperature, and the mixture was stirred at room temperature 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, methanol/ethyl acetate) to give the title compound (63.1 mg).