Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.Cl.O[C:10]1[C:15]2=[N:16][C:17]([CH3:24])=[C:18]([CH2:21][CH2:22][OH:23])[C:19](=[O:20])[N:14]2[CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>O>[OH:23][CH2:22][CH2:21][C:18]1[C:19](=[O:20])[N:14]2[CH:13]=[CH:12][CH:11]=[C:10]([O:6][CH3:7])[C:15]2=[N:16][C:17]=1[CH3:24]
Reactant: Cc1nc2c(O)cccn2c(=O)c1CCO
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccn2c(=O)c(CCO)c(C)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
Dimethyl sulfate (2.52 g) was added dropwise to a mixture of intermediate 9 (4.4 g) and sodium hydroxide (0.8 g) in water (10 ml), while cooling in ice water. The reaction mixture was stirred for 15 minutes at RT, then it was heated for 1 hour using a warm water bath. The reaction mixture was cooled and extracted with CH2Cl2. The precipitate in the separated aqueous layer was filtered off and purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 97/3). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN. The crystals were filtered off and dried, yielding 2 g (42%) of 3-(2-hydroxyethyl)-9-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (intermediate 10).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=O)[NH:10][C:5]2=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:18]([NH:20][NH2:21])=[O:19].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([NH:21][NH:20][C:18](=[O:19])[C:17]3[CH:22]=[CH:23][C:24]([Cl:25])=[C:15]([Cl:14])[CH:16]=3)=[O:13])[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2nc(Cl)ccc2[nH]1
Reactant: NNC(=O)c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NNC(=O)c1cc2nc(Cl)ccc2[nH]1)c1ccc(Cl)c(Cl)c1
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (Preparation 5, 20.0 mg, 0.10 mmol) in DMF (5 mL) was added 3,4-dichlorobenzoic acid hydrazide (23 mg, 0.11 mmol), DIPEA (19.5 μL, 0.11 mmol) and HOBt (14.0 mg, 0.10 mmol). The resulting solution was stirred for 5 min prior to the addition of EDCI (23 mg, 1.20 mmol). The reaction mixture was stirred for 16 hr at rt then partitioned between water (10 mL) and dichloromethane (20 mL) on a hydrophobic frit. The aqueous phase was extracted with a further portion of dichloromethane (30 mL) and the combined organics were concentrated in vacuo. Trituration of the resulting residue with ethyl acetate/dichloromethane gave the title compound. δH (d6 DMSO): 12.25 (1H, s), 10.83 (2H, d), 8.17 (1H, s), 7.55-7.97 (3H, m), 7.38 (1H, s), 7.26 (1H, d); m/z (ES+)=383 [M+H]+; RT=3.37 min.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17][NH2:18])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCl>ClCCCl>[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17][NH:18][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.4 %

Procedure:
Benzaldehyde (3.3 ml, 32.4 mmol) was added to a stirred solution of tert-butyl-N-(2-aminoethyl)carbamate (5.19 g, 32.4 mmol) in 1,2-dichloroethane (50 ml). After stirring for 1 h sodium triacetoxyborohydride (10.3 g, 48.6 mmol) was added in two portions and the reaction mixture stirred at room temperature for a further 3 h. Dichloromethane (300 ml) was added and the mixture washed with 1N sodium hydroxide. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 50–100% ethyl acetate in hexane then 1–5% methanol in ethyl acetate to afford the title compound (4.9 g, 60%). Mass spectrum (AP+): Found 251 (MH+). C14H22N2O2 requires 250.
Reaction SMILES: [O:1]1[C@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:2]1.[F:10][C:11]([F:33])([F:32])[O:12][C:13]([F:31])([O:18][C:19]([F:30])([O:24][C:25]([F:29])([F:28])[CH2:26][OH:27])[C:20]([F:23])([F:22])[F:21])[C:14]([F:17])([F:16])[F:15].ClC[C@H](O)CCCCC=C.[OH-].[K+]>O.COCCOC>[F:10][C:11]([F:32])([F:33])[O:12][C:13]([F:31])([O:18][C:19]([F:30])([O:24][C:25]([F:29])([F:28])[CH2:26][O:27][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([OH:1])[CH3:2])=[CH2:9])[C:20]([F:22])([F:21])[F:23])[C:14]([F:17])([F:16])[F:15]
Reactant: C=CCCCC[C@@H]1CO1
Reactant: OCC(F)(F)OC(F)(OC(F)(OC(F)(F)F)C(F)(F)F)C(F)(F)F
Agent: C=CCCCC[C@@H](O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: C=C(CCCCC(C)O)OCC(F)(F)OC(F)(OC(F)(OC(F)(F)F)C(F)(F)F)C(F)(F)F
Temperature: 45 °C
Reaction time: 1 h

Procedure:
This chlorohydrin was converted in situ to (R)-1,2-epoxy-7-octene and reacted with 2-(2-(2-(trifluoromethoxy(tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol using the following procedure: (R)-8-chloro-7-hydroxy-oct-1-ene (100 g, 0.61 mol), aqueous potassium hydroxide (45 mL of 45 wt. %), 2-(2-(2-(trifluoromethoxy(tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol (291 g, 0.733 mol), Adogen™ 464 (60 g), and 1,2-dimethoxyethane (60 mL) were added to a one liter flask fitted with a mechanical stirrer, an addition funnel, a reflux condenser, and a thermometer. The resulting solution was stirred for one hour at 45° C. and then warmed to 60° C., at which time aqueous potassium hydroxide (70 mL of 45 wt %) was added dropwise. This solution was heated for 2 hours at 60° C. and then at 70° C. for 8 hours. Water (300 mL) was added, and the resulting organic phase was separated and washed with 7 weight % HCl (300 mL). The organic phase was again separated and was concentrated under reduced pressure (25 torr). The resulting crude product was then purified by silica gel chromatography using toluene as eluent to give 268 g of (R)-8-(2-(2-(2-(trifluoromethoxy(tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-7-hydroxyoct-1-ene.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[S:10][C:11]=2[C:12](=O)/[CH:13]=[CH:14]/N(C)C)=[CH:4][CH:3]=1.Cl.[NH2:28][C:29]([NH2:31])=[NH:30].[O-]CC.[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)[S:10][C:11]=2[C:12]2[CH:13]=[CH:14][N:28]=[C:29]([NH2:31])[N:30]=2)=[CH:25][CH:26]=1
Reactant: N=C(N)N
Reactant: CN(C)/C=C/C(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: Nc1nccc(-c2sc(-c3ccncc3)nc2Cc2ccc(Cl)cc2)n1
Yield: 62 %

Procedure:
To a solution of (E)-1-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-3-(dimethylamino)prop-2-en-1-one (93.0 mg, 0.242 mmol) in isopropyl alcohol (1.0 mL) was added guanidine hydrochloride (34.7 mg, 0.363 mmol) and sodium ethoxide (65.4 mg, 1.21 mmol) and the resulting mixture was heated to reflux for 3 days. The reaction was cooled and concentrated in vacuo. The residue was slurried in DCM (10 mL) and water (10 mL). The undissolved solids were filtered. This material was purified by preparative reverse phase chromatography to give 57 mg (62% yield) of the title compound as a white solid. LC/MS (FA) ES+ 380, 382. 1H NMR (300 MHz, DMSO-d6) δ 8.73-8.71 (m, 2H), 8.31 (d, 1H, J=5.1 Hz), 7.88-7.86 (m, 2H), 7.36-7.30 (m, 4H), 6.86 (bs, 2H), 6.84 (d, 1H, J=5.1 Hz), 4.56 (s, 2H).
Reaction SMILES: N1C=CC=CC=1.[Si:7](Cl)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH2:15]([C:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:16]=[CH2:17].O([Si](C(C)(C)C)(C)C)S(C(F)(F)F)(=O)=O>CN(C)C1C=CN=CC=1.C(#N)C>[CH2:15]([C:18]1([O:24][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:16]=[CH2:17]
Reactant: C=CCC1(O)CCCCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC#N
Product: C=CCC1(O[Si](C)(C)C(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Pyridine (11.7 mL, 145 mmol), 4-dimethylaminopyridine (DMAP, 0.59 g, 4.82 mmol) and tert-butyldimethylsilyl chloride (8.71 g, 57.8 mmol) were added to a solution of 1-allylcyclohexanol (48.2 mmol) in acetonitrile (120 mL). The reaction was heated at reflux overnight, then cooled to rt and concentrated to about 50 mL under reduced pressure. The solution was cooled to 0° C. and tert-butyldimethylsilyl triflate (13.3 mL, 57.8 mmol) was added. After the solution had stirred overnight at rt, additional tert-butyldimethylsilyl triflate (5.00 mL) was added and the solution was stirred for 6 h longer. The reaction was quenched with saturated aqueous sodium bicarbonate (120 mL) and extracted with dichloromethane (100 mL, then 2×75 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to give a colorless oil that was purified on a on a HORIZON High-Performance Flash Chromatography (HPFC) instrument (available from Biotage, Inc, Charlottesville, Va., USA) (silica gel, gradient elution with 0-5% ethyl acetate/hexanes) to afford [(1-allylcyclohexyl)oxy](tert-butyl)dimethylsilane as a colorless oil (11.96 g, 97%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2=[O:23])[C@H:15]2[C@H:6]1[C@@H:7]1[C:12]([CH2:13][C@H:14]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]O)=[CH:11][C:10](=[O:34])[CH2:9][CH2:8]1)(=[O:3])[CH3:2].[Cl:35]C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C(Cl)Cl>[C:1]([O:4][C@@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2=[O:23])[C@H:15]2[C@H:6]1[C@@H:7]1[C:12]([CH2:13][C@H:14]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][Cl:35])=[CH:11][C:10](=[O:34])[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(=O)O[C@@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2[C@H](CCCCCCCCCO)CC3=CC(=O)CC[C@@H]3[C@H]21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)O[C@@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2[C@H](CCCCCCCCCCl)CC3=CC(=O)CC[C@@H]3[C@H]21
Reaction time: 5 h

Procedure:
15.8 g of 11α-acetoxy-7α-(9-hydroxynonyl)-estr-4-ene-3,17-dione is reacted in 65 ml of acetonitrile with 184 ml of tetrachloromethane and 17.9 g of triphenylphosphine at room temperature. After 5 hours, it is diluted with methylene chloride, washed neutral with saturated sodium bicarbonate solution and water and dried. The crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient. Yield: 7.8 g of 11α-acetoxy-7α-(9-chlorononyl)-estr-4-ene-3,17-dione with a melting point of 113-115° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[OH:25][C@@H:26]([CH2:39][NH2:40])[CH2:27][O:28][C:29]1[C:37]2[NH:36][C:35](=[O:38])[NH:34][C:33]=2[CH:32]=[CH:31][CH:30]=1>>[OH:25][C@H:26]([CH2:27][O:28][C:29]1[C:37]2[NH:36][C:35](=[O:38])[NH:34][C:33]=2[CH:32]=[CH:31][CH:30]=1)[CH2:39][NH:40][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:23][CH:24]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(S(=O)(=O)c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Product: O=C1NC(=O)C(Cc2ccc(S(=O)(=O)N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-sulfonyl)-benzyl]-thiazolidine-2,4-dione and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one according to the reductive amination procedure of Intermediate 21 as a pale grey solid; 1H NMR (300 MHz, DMSO-d6): δ 1.20-1.40 (m, 2 H), 1.80-2.00 (m, 2 H), 2.30-4.00 (m, 12 H), 4.65 (dd, J=8.0, 3.5 Hz, 1 H), 6.56 (d, J=3.2 Hz, 1 H), 6.59 (d, J=3.8 Hz, 1 H), 6.85 (t, J=3.5 Hz, 1 H), 7.50 (d, J=8.1 Hz, 2 H), 7.66 (d, J=8.1 Hz, 2 H), 10.70 (s, 1 H), 10.79 (brs, 1 H); MS (ES) m/z : 576.0 (M++H); HRMS Calcd. for C25H30N507S2 (M++H): 576.1587. Found: 576.1596.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:9])[CH3:8])[CH:2]=1.[Br:11]Br.CCOCC>O1CCOCC1>[Br:11][CH2:8][C:7]([C:3]1[CH:2]=[C:1]([CH3:10])[CH:6]=[CH:5][CH:4]=1)=[O:9]
Reactant: BrBr
Reactant: CC(=O)c1cccc(C)c1
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-m-tolyl-ethanone (6.0 g, 44.72 mmol) in dioxane (5 ml), bromine (7.14 g, 44.72 mmol) in dioxane (10 ml) and ether (15 ml) was added and stirred at room temperature for 5 hr. The reaction mixture was poured into ice water and the compound was extracted using ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and then evaporated to give crude 2-bromo-1-m-tolyl-ethanone, 7.6 g (80%). The crude compound obtained was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[N:21]=[C:22]([NH:25][C:26]3[N:31]=[CH:30][C:29]([S:32]CCC(OC)=O)=[CH:28][C:27]=3[O:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[S:23][CH:24]=2)[CH2:16][CH2:15]1)(=[O:13])[CH3:12].CC([O-])(C)C.[K+]>CS(C)=O>[O:39]([C:27]1[C:26]([NH:25][C:22]2[S:23][CH:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:11](=[O:13])[CH3:12])[CH2:19][CH2:18]3)[N:21]=2)=[N:31][CH:30]=[C:29]([S:32][C:2]2[C:3]3[CH:10]=[CH:9][S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:28]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: Clc1ncnc2sccc12
Reactant: COC(=O)CCSc1cnc(Nc2nc(C3CCN(C(C)=O)CC3)cs2)c(Oc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2csc(Nc3ncc(Sc4ncnc5sccc45)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
4-chlorothieno[2,3-d]pyrimidine (0.050 g, 0.29 mmol) and methyl 3-(6-(4-(1-acetylpiperidin-4-yl)thiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate (Example 3, Step B, 0.15 g, 0.29 mmol) were dissolved in DMSO (3 mL). The solution was degassed for 15 minutes. KOtBu (0.098 g, 0.88 mmol) was added and the reaction stirred at ambient temperature for two hours. The solution was quenched with water, extracted with dichloromethane, dried, and concentrated. Flash chromatography of the crude material gave the title compound (0.075, 46%). 1H NMR (400 MHz, CDCl3) δ 1.60-1.72 (m, 2H), 2.08-2.15 (m, 2H), 2.11 (m, 3H), 2.65-2.75 (m, 1H), 2.82-2.93 (m, 1H), 3.15-3.24 (m, 1H), 3.91 (d, 1H), 4.72 (d, 1H), 6.49 (s, 1H), 7.15 (d, 2H), 7.19 (t, 1H), 7.27-7.29 (m, 1H), 7.36-7.42 (m, 3H), 7.53 (d, 1H), 8.27 (d, 1H), 8.68 (s, 1H), 8.81 (s, 1H),
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:31][CH:32]1[O:36][CH2:35][CH2:34][O:33]1>>[N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:31][CH:32]6[O:36][CH2:35][CH2:34][O:33]6)[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1
Reactant: BrCC1OCCO1
Product: O=c1c2ccc(OCC3OCCO3)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1

Procedure:
2-((R)-4-[1,3′]Bipyrrolidinyl-1′-yl-3-fluoro-phenyl)-6-hydroxy-2H-isoquinolin-1-one was reacted with 2-Bromomethyl-[1,3]dioxolane by method K. The product with the molecular weight of 479.56 (C27H30FN3O4) was obtained in this way; MS (ESI): 480 (M+H+).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:25]1[C:33]2[C:28](=[CH:29][C:30]([NH2:34])=[CH:31][CH:32]=2)[CH:27]=[N:26]1.CN1C2C(=CC=C(N)C=2)C=N1.CN1C2C(=CC(N)=CC=2)C=N1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:34][C:30]4[CH:29]=[C:28]5[C:33](=[CH:32][CH:31]=4)[NH:25][N:26]=[CH:27]5)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: Cn1ncc2cc(N)ccc21
Agent: Cn1ncc2ccc(N)cc21
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc5[nH]ncc5c4)nn23)c1

Procedure:
Following the procedure of Example 1311c, N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (225 mg, 0.650 mmol) was coupled in parallel fashion with 1H-indazol-5-ylamine (36 mg, 0.27 mmol), [1-methyl-1H-indazol-6-ylamine (43 mg, 0.29 mmol), and 1-methyl-1H-indazol-5-ylamine (41 mg, 0.28 mmol). After evaporation of solvent, residues were purified with ISCO chromatography unit outfitted with a 12 g silica gel column and eluted with a gradient of DCM/MeOH to afford titled products. Yield: 38 mg (13%); LC/MS: 462 (M+H); HPLC: 97% pure, RT=3.11 min; 1H NMR: (DMSO, δ) 12.92 (s, 1H), 9.55 (s, 1H), 9.04 (s, 1H), 8.49 (m, 2H), 8.25 (s, 1H), 8.02 (s, 1H), 7.88 (d, J=8.2, 1H), 7.77 (t, J=8.2, 1H), 7.61 (m, 2H), 7.51 (d, J=8.7, 1H), 7.18 (d, J=4.7, 1H), 6.99 (d, J=4.7, 1H), 1.10 (s, 9H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:24][C:25]1[C:26]([C:33]([NH:35][C:36](SC)=[NH:37])=[O:34])=[N:27][C:28]([Cl:32])=[C:29]([NH2:31])[N:30]=1.C(N(C(C)C)CC)(C)C>CCO>[NH2:24][C:25]1[C:26]([C:33]([NH:35][C:36](=[NH:37])[NH:23][CH2:22][CH2:21][CH2:20][CH2:19][C:14]2[CH:13]=[CH:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:10]=3)[CH:15]=2)=[O:34])=[N:27][C:28]([Cl:32])=[C:29]([NH2:31])[N:30]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(CCCCN)ccc2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(CCCCNC(=N)NC(=O)c3nc(Cl)c(N)nc3N)ccc2c1
Temperature: 70 °C
Yield: 50.6 %

Procedure:
To a solution of amine 77 (337 mg, 1.02 mmole) and methyl 3,5-diamino-6-chloropyrazine-2-carbonylcarbamimidothioate (10, 596 mg, 1.53 mmole) in EtOH (20 mL) was added diisopropylethylamine (1.06 mL, 6.13 mmole) at room temperature. The reaction mixture was heated at 70° C. in a sealed tube for 6 h, then cooled to room temperature, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 80:18:2 CHCl3/CH3OH/NH4OH) to afford carboxamide 78 (280 mg, 50%) as a light yellow solid: 1H NMR (300 MHz, CD3OD) δ 7.67 (d, J=9.2 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.57 (br s, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.14 (br s, 1H), 7.03 (dd, J=9.2, 1.7 Hz, 1H), 3.30 (m, 2H), 2.81 (t, J=7.0 Hz, 2H), 1.95-1.62 (m, 4H), 1.03 (s, 9H), 0.24 (s, 6H).
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([O:11][C:12]([C:14]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:18][CH2:17][NH:16][CH2:15]1)=[O:13])[CH3:10]>>[CH2:9]([O:11][C:12]([C:14]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)[CH2:18][CH2:17][N:16]([C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])[CH2:15]1)=[O:13])[CH3:10]
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Reactant: O=C(Cl)C1CCCC1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)C2CCCC2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 76 using cyclopentanecarbonyl chloride and 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 65) to afford the racemate as a white solid (120 mg, 94%)
Reaction SMILES: [CH2:1]([C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C:8]1=[CH:7][CH2:6][C:5]12[O:26][CH2:25][CH2:24][O:23]1)[CH2:2][CH3:3].[H][H]>C1C=CC=CC=1.[Pd]>[CH2:1]([C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C@@H:8]1[CH2:7][CH2:6][C:5]12[O:23][CH2:24][CH2:25][O:26]1)[CH2:2][CH3:3]
Reactant: CCC[C@]12CCC3=C(CCc4cc(OC)ccc43)C1=CCC21OCCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccccc1
Product: CCC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CCC21OCCO1
Yield: 71.6 %

Procedure:
Shake 13β-Propyl-3-methoxy-17,17-ethylenedioxygona-1,3,5(10),8,14-pentaene (2.5 g.) in benzene (80 cc.) with hydrogen at atmospheric pressure in the presence of a 2% palladium on calcium carbonate catalyst (0.9 g.); hydrogen uptake ceases after the requisite amount (161 cc.) for monohydrogenation has been absorbed. Filter and evaporate to obtain a gum, which one crystallizes from ethanol to obtain the title product (1.8 g.), m.p. 119°-120°; ultraviolet absorption peak at 278 mμ (ε15,300).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[C:8]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccccn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-trifluoromethylsulfanyl-phenyl)propionic acid (59.6 mg, 0.187 mmol) and triphenylphosphine (49.1 mg, 0.187 mmol) in methylene chloride (468 μL) was cooled to 0° C. and then treated with N-bromosuccinimide (36.7 mg, 0.206 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The orange reaction mixture was then treated with 2-aminopyridine (35.2 mg, 0.374 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining residue was diluted with ethyl acetate (50 mL). The organic layer was washed sequentially with a 10% aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and water (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 9/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethylsulfanyl-phenyl)-propionamide (25.0 mg, 34%) as a cream solid: mp 101–102° C.; EI-HRMS m/e calcd for C20H21F3N2OS (M+) 394.1327, found 394.1321.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[S:34][CH:35]=[CH:36][C:37]=1[CH3:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:38][C:37]1[CH:36]=[CH:35][S:34][C:33]=1[CH2:32][N:7]1[C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: Cc1ccsc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccsc1Cn1c(=O)n(C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c2sc(-c3ccccc3)cc21

Procedure:
According to the procedure described for compound B71 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (1.09 g, compound B50) is reacted with 2-(chloromethyl)-3-methylthiophene (410 mg, compound D28) in the presence of potassium carbonate (778 mg) in dry DMF (14 ml) for 1 h at 100° C. to afford the title compound as a solid.