Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.ClC1C=C([C:18]2[C:23]3[N:24]([CH2:36][C@H:37]4[CH2:42][CH2:41][C@H:40]([CH3:43])[CH2:39][CH2:38]4)[C:25](N4C[C@H](OC)C[C@H]4CO)=[N:26][C:22]=3[CH:21]=[C:20]([C:44]#[N:45])[N:19]=2)C=NC=1.C(N(CC)CC)C>ClCCl>[CH3:43][C@H:40]1[CH2:41][CH2:42][C@H:37]([CH2:36][N:24]2[C:23]3[CH:18]=[N:19][C:20]([C:44]#[N:45])=[CH:21][C:22]=3[N:26]=[CH:25]2)[CH2:38][CH2:39]1
Reactant: CO[C@@H]1C[C@@H](CO)N(c2nc3cc(C#N)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C[C@H]1CC[C@H](Cn2cnc3cc(C#N)ncc32)CC1
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
A solution of oxalyl chloride (0.160 ml, 1.826 mmol) in dichloromethane (5 ml) was cooled to −78° C., and a solution of DMSO (0.259 ml, 3.65 mmol) in dichloromethane (2.5 ml) was slowly added. The reaction was warmed to −60° C. After 10 min of stirring, a solution of 4-(5-chloropyridin-3-yl)-2-((2S,4R)-2-(hydroxymethyl)-4-methoxypyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (452 mg, 0.913 mmol) in dichloromethane (5 ml) was slowly added. The reaction was stirred for 30 min at −40° C. Then triethylamine (0.764 ml, 5.48 mmol) was added, and the reaction was warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous NaHCO3 (30 mL). The dichloromethane layer was separated. The aqueous layer was extracted with dichloromethane (20 mL). The combined dichloromethane layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane to give 4-(5-chloropyridin-3-yl)-2-(2S,4R)-2-formyl-4-methoxypyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C26H29ClN6O2 [M+H]+ 493. found 493.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([NH:16][C:17]2[C:18]([N:26]3[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32]C(=O)OC(C)(C)C)[CH2:27]3)=[C:19]3[CH2:25][CH2:24][CH2:23][C:20]3=[N:21][CH:22]=2)=[O:15])[N:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO.[NH4+].[OH-]>[NH2:32][C@H:28]1[CH2:29][CH2:30][CH2:31][N:26]([C:18]2[C:17]([NH:16][C:14]([C:12]3[N:13]=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[S:10][CH:11]=3)=[O:15])=[CH:22][N:21]=[C:20]3[CH2:23][CH2:24][CH2:25][C:19]=23)[CH2:27]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3c2CCC3)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3c2CCC3)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
tert-Butyl {(3S)-1-[3-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate (4 mg, 0.007 mmol) was dissolved in DCM (0.02 mL) and then TFA (0.03 mL, 0.4 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min. and then concentrated to give a residue, which was diluted with MeOH and neutralized with small amount of NH4OH. The mixture was filtered and purified by preparative LC-MS (XBridge™ preparative C18 30×10 mm, 5 m OBD™ column, at flow rate of 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to afford the title compound (1.9 mg, 58%). LCMS calc. for C23H24F2N5OS (M+H)+: m/z=456.2. Found: 456.1.
Reaction SMILES: C1(NS(O)(=O)=O)CCCCC1.[CH2:12]([N:14]([CH2:38][CH3:39])[CH2:15][CH2:16][N:17]([CH3:37])[C:18]([C:20]1N(C)[C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:23]2[C:28]=1[CH:27]=[CH:26][C:25]([Cl:29])=[CH:24]2)=[O:19])[CH3:13].[OH-:40].[NH4+].[OH2:42]>>[CH2:12]([N:14]([CH2:38][CH3:39])[CH2:15][CH2:16][N:17]([CH3:37])[C:18](=[O:19])[C:20]([C:28]1[CH:27]=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=1[C:22](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:40])[CH3:13]
Reactant: [OH-]
Reactant: O
Reactant: CCN(CC)CCN(C)C(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Agent: O=S(=O)(O)NC1CCCCC1
Agent: [NH4+]
Product: CCN(CC)CCN(C)C(=O)C(=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A solution of 34.6 g. of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid[ 2-(diethylamino)ethyl]-methylamide cyclohexanesulfamate in 400 ml. of water is treated with excess 2-N ammonium hydroxide. The liberated base is extracted with methylene chloride and the extract evaporated to dryness. To the obtained residue, there is added a solution of 86.4 g. of ceric ammonium nitrate in 150 ml. of water and 150 ml. of glacial acetic acid. The mixture is stirred at 80° C. for 20 minutes, the color of the solution obtained changing from orange to light yellow. After cooling, 750 ml. of ice-water are added and the separated oil is extracted with methylene chloride. The organic phase is washed with 2-N ammonium hydroxide and a saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness. o-benzoyl-p-chlorophenylglyoxylic acid[ 2-(diethylamino)ethyl]methylamide is obtained as an oil which can be used in the process without further purification. With 2 mols of N-cyclohexylsulfamic acid, the base forms an addition compound which melts at 136°-138° C. (decomposition) after crystallization from isopropanol/diethyl ether.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][PH:11](=[O:15])[O:12][CH2:13][CH3:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([P:11]([CH3:10])(=[O:15])[O:12][CH2:13][CH3:14])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCO[PH](C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(C)(=O)c1ccc(C=O)cc1
Temperature: 110 °C
Reaction time: 10 h

Procedure:
To a solution of 4-bromobenzaldehyde, 38-a, (500 mg, 2.7 mmol) and ethyl methylphosphinate, 38-b, (650 mg, 5.4 mmol) in toluene (10 mL) was added triethylamine (1.1 g, 11 mmol). After being allowed to stir for 10 h at 110° C. under nitrogen atmosphere, the mixture was cooled to ambient temperature, concentrated, diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (2×30 mL), dried over Na2SO4, filtrated and concentrated to give a residue, which was purified by chromatography on silica gel (dichloromethane/methanol=70:1) to afford compound 38-c as a colorless oil. (530 mg, 93%). 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.93-8.05 (m, 4H), 3.90-3.98 (m, 2H), 1.68-1.73 (d, J=14.4 Hz, 3H), 1.16-1.24 (m, 3H). LC-MS 213 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:14][N:13]([CH2:15][C:16](O)=[O:17])[C:12](=[O:19])[CH:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:10]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:9]1=2.[NH:29]1[CH2:34][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:9]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:10]=2[CH:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:12](=[O:19])[N:13]([CH2:15][C:16]([N:29]2[CH2:34][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]2)=[O:17])[CH2:14]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)CC1C(=O)N(CC(=O)O)CC(c2ccccc2Br)c2cc(Cl)ccc21
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(=O)CN2CC(c3ccccc3Br)c3cc(Cl)ccc3C(CC(C)C)C2=O)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
190 mg of the compound from Example 6 (0.39 mol) and 65 mg of ethyl piperidine-4-carboxylate (0.41 mol) are dissolved in 5.0 ml of dimethylformamide, and 75 mg of diethyl cyanophosphonate (0.43 mol) and 81 μl of triethylamine (59 mg, 0.58 mol) are added. The reaction mixture is stirred at room temperature for 2.5 h, then mixed with ethyl acetate and washed with 5% strength potassium bisulphate solution, saturated sodium bicarbonate solution and saturated sodium chloride. The organic phase is dried over sodium sulphate, the solvent is removed in a rotary evaporator, and the residue is purified by preparative HPLC (eluent: acetonitrile/water, gradient 20:80→95:5). 204 mg (87% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:4]([CH:9]([OH:11])[CH3:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:14]Br>CO>[Br:14][C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:12])[F:13])[C:4]([CH:9]([OH:11])[CH3:10])=[N:5][CH:6]=1
Reactant: BrBr
Reactant: CC(O)c1ncccc1C(F)(F)F
Solvent: CO
Product: CC(O)c1ncc(Br)cc1C(F)(F)F

Procedure:
Dissolve 1-(3-(trifluoromethyl)pyridin-2-yl)ethanol (8.8 g, 0.046 moles) in anhydrous MeOH (80 mL) and add bromine (2.35 mL) dropwise at room temperature. Reflux the mixture under N2 atmosphere for 3 weeks with the addition of bromine (1.0 mL) on each day. Concentrate the reaction mixture under vacuum, dilute with water (100 mL), neutralize with NaHCO3, extract with EtOAc (3×100 mL) and dry (MgSO4). Filter the dried extract and concentrate under vacuum to afford a yellow oil. Purify the crude product by column chromatography to afford the title compound as a pale yellow oil.
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[CH:8]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([F:21])=[CH:18][C:19]=2[F:20])=[CH:12][C:11]([C:22]([OH:24])=[O:23])=[C:10]([OH:25])[CH:9]=1>CO>[CH3:2][O:23][C:22]([C:11]1[CH:12]=[C:13]([C:14]2[CH:15]=[CH:16][C:17]([F:21])=[CH:18][C:19]=2[F:20])[CH:8]=[CH:9][C:10]=1[OH:25])=[O:24]
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
Compounds 32 and 33 were prepared according to Scheme 6. TMS-diazomethane (5.87 mL, 11.75 mmol, 2 M solution in hexane) was added to a solution of diflunisal (1.03 g, 4.11 mmol) in MeOH (10 mL) and stirred at rt for 5 h. Upon completion, the reaction was concentrated in vacuo and the residue was purified by flash chromatography (10:1 hexane:ethyl acetate) to afford 32 (774 mg, 71%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.97 (dd, 1H, J=2.2, 1.3 Hz), 7.59 (dt, 1H, J=8.8, 2.1 Hz), 7.36 (dq, 1H, J=7.7, 1.5 Hz), 7.48 (td, 1H, J=7.8, 1.7 Hz), 7.38 (dddd, 1H, J=8.8, 6.4 Hz), 7.05 (d, 1H, J=8.7 Hz), 6.93 (m, 1H), 6.90 (ddd, 1H, J=10.6, 8.9, 2.5 Hz), 3.96 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 170.6, 163.6, 161.3, 158.5, 136.4, 131.2, 130.3, 126.2, 124.2, 118.0, 112.6, 111.8, 104.6, 52.6, 124.2. HRFABMS calculated for C14H10F2O3 (M+) 264.0596. found 264.0598. Normal phase HPLC retention time: 6.9 min. Reverse phase HPLC retention time: 14.7 min. >99% pure.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:12](=[CH:13][N:14]=1)[NH:11][C:10](=[O:15])[CH:9]1[CH2:16][N:5]2[CH2:6][CH2:7][CH2:8]1.[C:17](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]2[C:12](=[CH:13][N:14]=1)[N:11]([CH3:17])[C:10](=[O:15])[CH:9]1[CH2:16][N:5]2[CH2:6][CH2:7][CH2:8]1
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2cnc(Cl)nc2N2CCCC1C2
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C2CCCN(C2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.075 g (0.00032 mole) of (rac)-4-chloro-1,3,5,8-tetraaza-tricyclo[8.3.1.0*2,7*]tetradeca-2,4,6-trien-9-one (VI-67), 0.8 mL of dimethylformamide, 0.17 g (0.0005 mole) of cesium carbonate and 0.055 g (0.0004 mole) of iodomethane was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give (rac)-4-chloro-8-methyl-1,3,5,8-tetraaza-tricyclo[8.3.1.0*2,7*]tetradeca-2,4,6-trien-9-one (VII-67), which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[F:11][C:12]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].C([O-])([O-])=O.[K+].[K+].[CH:26]([C:29]1[N:33]=[C:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[O:31][N:30]=1)([CH3:28])[CH3:27]>CN(C=O)C.O.CCOC(C)=O>[F:11][C:12]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:37]2[CH2:36][CH2:35][CH:34]([C:32]3[O:31][N:30]=[C:29]([CH:26]([CH3:28])[CH3:27])[N:33]=3)[CH2:39][CH2:38]2)[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(Cl)ncnc1Cl
Reactant: CC(C)c1noc(C2CCNCC2)n1
Reactant: Nc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1noc(C2CCN(c3ncnc(Nc4cccc(F)c4F)c3C#N)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4,6-dichloro-pyrimidine-5-carbonitrile (254 mg, 1.47 mmol) and 2,3-difluoroaniline (190 mg, 1.47 mmol) in DMF (3 mL) at 0° C. was added K2CO3 (203 mg, 1.47 mmol). The completion of the reaction was monitored by TLC (EtOAc:Hex 1:1, Rf=0.90). After the completion of the reaction, 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine (340 mg, 1.47 mmol) and K2CO3 (406 mg, 2.94 mmol) were added at 0° C. The reaction was warmed to rt and stirred for 30 min. The reaction was heated to 40° C. and maintained for 1 h. The reaction was cooled to rt, poured in to H2O (50 mL) and extracted with EtOAc (50 mL, two times). The EtOAc was dried over MgSO2 and concentrated under vacuum. The crude product was purified over SiO2 (EtOAc:Hex=1:1, Rf=0.49) to afford Compound B130 (501 mg; 76.7%). 1H-NMR (DMSO-d6): 9.60 (1H, s), 8.28 (1H, s), 7.45˜7.29 (3H, m), 4.64 (2H, m), 3.59˜3.52 (4H, m), 3.41˜3.49 (2H, m), 2.29˜2.25 (2H, b), 1.96˜1.86 (2H, m), 1.39 (6H, d) ppm. LCMS: 426.43.
Reaction SMILES: [N:1]([C@H:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([F:21])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5]1)=[N+:2]=[N-:3].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([C@H:39]([CH2:44][C:45]#[CH:46])[C:40]([O:42][CH3:43])=[O:41])=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.O>[CH:31]1[C:32]2[CH:33]([CH2:35][O:36][C:37]([CH:39]([CH2:44][C:45]3[N:3]=[N:2][N:1]([C@H:4]4[C:13]5[C:8](=[CH:9][C:10]([CH2:14][N:15]6[CH2:16][CH2:17][CH:18]([F:21])[CH2:19][CH2:20]6)=[CH:11][CH:12]=5)[O:7][CH2:6][CH2:5]4)[CH:46]=3)[C:40]([O:42][CH3:43])=[O:41])=[O:38])[C:34]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: C#CC[C@H](C(=O)OC)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: [N-]=[N+]=N[C@@H]1CCOc2cc(CN3CCC(F)CC3)ccc21
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)C(Cc1cn([C@@H]2CCOc3cc(CN4CCC(F)CC4)ccc32)nn1)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred mixture of (R)-1-((4-azido-3,4-dihydro-2H-chromen-7-yl)methyl)-4-fluoropiperidine (0.83 g, 2.9 mmol) and (R)-methyl 2-(((9H-fluoren-9-yl)methoxy)-carbonyl)pent-4-ynoate (1.0 g, 2.9 mmol) in t-BuOH/H2O (1:1, 40 mL) was added a solution of sodium ascorbate (30 mg, 0.14 mmole) in H2O (300 μL), followed by CuSO4.5H2O (7 mg, 0.03 mmol) in H2O (300 μL). The reaction mixture was stirred for 72 h at RT. The reaction mixture was concentrated, extracted with CH2Cl2 (3×), dried over MgSO4, and concentrated. The residue was purified by SiO2 (2% MeOH/CH2Cl2) to give the title compound. MS (m/z): 640.4 (m+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([O:20][CH3:21])=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[N:7]([CH2:22][CH2:23][CH2:24][C:25](OCC)=[O:26])[C:6]=2[C:5]([CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([O:20][CH3:21])=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[N:7]([CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:6]=2[C:5]([CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2ccc(OC)nc2OC)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(OC)nc3OC)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 36 h
Yield: 64.1 %

Procedure:
To a solution of ethyl 4-[4-chloro-2-[(2,6-dimethoxypyridin-3-yl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (120 mg, 0.245 mmol) in tetrahydrofuran (3 mL) was added lithium borohydride (16 mg, 0.736 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 36 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (70 mg, 0.157 mmol, 64%) as a pale blue solid.
Reaction SMILES: [Cs].[CH3:2][CH:3]([CH3:15])[CH2:4][CH2:5][CH:6]1[N:10]([CH3:11])[S:9](=[O:13])(=[O:12])[NH:8][C:7]1=[O:14].[C:16]1([S:22][CH2:23]Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[C:16]1([S:22][CH2:23][N:8]2[C:7](=[O:14])[CH:6]([CH2:5][CH2:4][CH:3]([CH3:15])[CH3:2])[N:10]([CH3:11])[S:9]2(=[O:13])=[O:12])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCSc1ccccc1
Reactant: CC(C)CCC1C(=O)NS(=O)(=O)N1C
Agent: [Cs]
Solvent: CN(C)C=O
Product: CC(C)CCC1C(=O)N(CSc2ccccc2)S(=O)(=O)N1C
Temperature: 85 °C
Yield: 68.1 %

Procedure:
A mixture of 4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide cesium salt (prepared by reacting 7.7 g (34.95 mmol) of the dioxide in methanol with 5.13 g of Cs2CO3 followed by removal of solvent) and phenylthiomethyl chloride (6.65 g, 41.94 mmol) suspended in DMF was heated at 85° C. for 17 hours. The mixture was cooled, and poured into 300 ml of ice/water. The reaction mixture was extracted with ethyl acetate (3x) and the organic layer was washed with water and brine and dried over sodium sulfate. The organic layer was concentrated in vacuo and the residue was purified by silica column chromatography (10% ethyl acetate in hexane) to afford 8.15 g (70.6%) of 2-phenylthiomethyl-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =H; R2 =(CH2)2CH(CH3)2 ; R3 =CH3) as an oil.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][C:10]=2[CH:18]=[CH2:19])=[CH:5][CH:4]=1.[O:20]=[C:21]1[CH2:25][N:24]([C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:27])[C@H:23]([C:35]([O:37][CH3:38])=[O:36])[CH2:22]1>C1COCC1.C(Cl)Cl>[CH3:16][N:15]([CH3:17])[C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C@@:21]3([OH:20])[CH2:25][N:24]([C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])=[O:27])[C@H:23]([C:35]([O:37][CH3:38])=[O:36])[CH2:22]3)=[CH:4][CH:5]=2)=[C:10]([CH:18]=[CH2:19])[CH:11]=1
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OCC[Si](C)(C)C
Reactant: C=Cc1cc(N(C)C)ccc1-c1ccc(Br)cc1
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=Cc1cc(N(C)C)ccc1-c1ccc([C@]2(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)cc1
Reaction time: 0.5 h
Yield: 26.6 %

Procedure:
Magnesium (62 mg, 2.55 mmol) was stirred in a round bottom flask under N2 for 15 min. to cause scratching of the surface of the magnesium turnings. 10 mL of THF was added to the magnesium turnings and stirred for an additional 30 min. 4′-bromo-N,N-dimethyl-2-vinylbiphenyl-4-amine (735 mg, 2.432 mmol) in THF (20 mL), was added dropwise at reflux with vigorous stirring. The Grignard solution was added to a solution of (S)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-oxopyrrolidine-1,2-dicarboxylate (699 mg, 2.432 mmol) in DCM (20 mL) at r.t. and stirred for 1 hr and then quenched with sat. NH4Cl solution. The aqueous layer was extracted with DCM and the combined organics were dried, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (10-40% EtOAc:Hex) to give (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-(4′-(dimethylamino)-2′-vinylbiphenyl-4-yl)-4-hydroxypyrrolidine-1,2-dicarboxylate (330 mg, 0.646 mmol, 27% yield) as a yellow foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.04 (s, 9H) 0.99-1.11 (m, 2H) 2.34-2.52 (m, 1H) 2.62-2.81 (m, 1H) 3.00-3.07 (m, 6H) 3.68-3.81 (m, 1H) 3.82-3.89 (m, 3H) 4.17-4.34 (m, 3H) 4.49-4.68 (m, 1H) 5.19 (dd, J=11.04, 1.25 Hz, 1H) 5.70 (dd, J=17.57, 1.25 Hz, 1H) 6.67-6.80 (m, 2H) 6.96 (d, J=2.26 Hz, 1H) 7.16-7.22 (m, 1H) 7.34 (m, 2H) 7.49 (m, J=8.28 Hz, 2H). LCMS: rt=1.71 min. [M+H]+=511; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]=[C:17]([CH2:46][CH2:47][CH3:48])[N:18]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:34][CH:33]=2)[C:19](=[O:30])[C:20]=1[O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]1[N:16]=[C:17]([CH2:46][CH2:47][CH3:48])[N:18]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[NH:3][C:4](=[O:7])[O:5][N:45]=3)=[CH:34][CH:33]=2)[C:19](=[O:30])[C:20]=1[O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)c(Oc2ccc(CC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(Oc2ccc(CC)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.72 g), sodium hydrogen carbonate (1.03 g) and dimethyl sulfoxide (12 mL) was stirred at 40° C. for 30 min, 4′-{[4-ethyl-5-(4-ethylphenoxy)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.59 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.3 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.47 g, 71%).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[NH:36]1[CH:40]=[CH:39][CH:38]=[N:37]1>>[C:1]([C:3]1([NH:6][C:7]([CH:9]2[CH2:13][CH:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:36]4[CH:40]=[CH:39][CH:38]=[N:37]4)=[CH:19][C:18]=3[C:24]([F:26])([F:27])[F:25])(=[O:16])=[O:15])[CH2:11][CH:10]2[C:28]([N:30]2[CH2:33][C:32]([F:34])([F:35])[CH2:31]2)=[O:29])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Reactant: c1cn[nH]c1
Product: N#CC1(NC(=O)C2CC(S(=O)(=O)c3ccc(-n4cccn4)cc3C(F)(F)F)CC2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to Example 127 using (1R,2R,4R)-2-(3,3-Difluoro-azetidine-1-carbonyl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 118) and pyrazole. White foam. MS (EI): 572.14 (M+H)+.