Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9](S(C)(=O)=O)=[N:8][C:6]=2[N:7]=1.[N:21]1([CH2:27][CH2:28][OH:29])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([N:24]3[CH2:25][CH2:26][N:21]([CH2:27][CH2:28][OH:29])[CH2:22][CH2:23]3)=[N:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: OCCN1CCNCC1
Product: OCCN1CCN(c2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
5-Chloro-2-(methylsulfonyl)-7-morpholinothiazolo[4,5-d]pyrimidine was reacted with 2-(piperazin-1-yl)ethanol, via General Procedure C, to give crude 2-(4-(5-chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)piperazin-1-yl)ethanol, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure C again to give 134 after purification by reverse HPLC. MS (Q1) 444 (M+)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49]([C:52]1[CH:53]=[C:54](B(O)O)[CH:55]=[CH:56][CH:57]=1)(=[O:51])[NH2:50]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:56]3[CH:55]=[CH:54][CH:53]=[C:52]([C:49](=[O:51])[NH2:50])[CH:57]=3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(Br)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(-c3cccc(C(N)=O)c3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1

Procedure:
Aryl halide 9 was coupled to 3-carbamoylphenylboronic acid to give 30 on a 0.1 mmol scale via General Procedure H (57 mg, 52%): δH (400 MHz, CDCl3) 2.38 (s, 3H, CH3), 2.81 (s, 3H, CH3), 3.68 (s, 2H, CH2), 4.83 (s, 2H, CH2), 5.02 (s, 2H, CH2), 5.34 (s, 2H, CH2), 5.93 (s, 1H, NH2), 6.33 (s, 2H, NH2), 6.64 (s, 1H, CH), 6.67 (dd, J=6.0 and 1.2 Hz, 1H, CH), 7.18 (d, J=6.0 Hz, 2H, CH), 7.31-7.39 (m, 13H, CH), 7.50 (d, J=6.0 Hz, 2H, CH), 7.60 (d, J=6.3 Hz, 2H, CH), 7.70 (d, J=5.7 Hz, 1H, CH), 7.77 (d, J=5.7 Hz, 1H, CH), 7.83 (d, J=6.0 Hz, 1H, CH), 8.03 (s, 1H, CH); δC (100 MHz, CDCl3) 21.3, 35.9, 51.3, 52.7, 66.9, 70.6, 113.9, 119.2, 119.9, 126.0, 126.9, 127.0, 127.2, 127.3, 127.9, 128.1, 128.1, 128.4, 128.4, 128.7, 128.9, 129.2, 129.4, 130.3, 132.3, 133.0, 133.8, 135.1, 135.5, 135.6, 136.0, 139.4, 140.8, 143.3, 144.8, 158.7, 165.2, 167.0, 169.1; LRMS (ES+) calcd for [C45H41N3O7S+H]768.27 found 768.27.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[O:16][C:17]([F:20])([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[O:23][C:24](C)=[O:25]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:24]([OH:25])=[O:23])=[CH:11][C:10]=1[O:16][C:17]([F:20])([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: FC(F)(F)Oc1cc(Br)ccc1OCc1ccccc1
Product: O=C(O)c1ccc(OCc2ccccc2)c(OC(F)(F)F)c1

Procedure:
4-Benzyloxy-3-trifluoromethoxybenzoic acid was prepared from 4-benzyloxy-1-bromo-3-trifluoromethoxybenzene by following Method M. The crude product was purified by crystallization using a mixture of EtOAc and hexanes as a solvent (19% yield of desired product from the first crop).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.CO.[H][H]>[Pd]>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc(C)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(C)cc1
Yield: 88.2 %

Procedure:
1.39 g of 3-p-tolyl-acrylic acid methyl ester (40aa) prepared by above Step 1 was dissolved in methanol solution (7.9 mmol) under argon atmosphere. Then Pd—C was added thereto, hydrogenated under a hydrogen balloon for 1 to 2 hrs at room temperature. The reaction mixture was filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with a solvent mixture mixed with EtOAc and hexane (1:10) as an eluant to give 1.24 g of 3-p-tolyl-propionic acid methyl ester (40ab) (yield: 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:17]C)[C:8](=O)[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[S:4]1.[OH-].[Na+]>Cl>[CH3:10][C:6]1[N:7]=[C:8]([C:3]([O:2][CH3:1])=[O:17])[S:4][C:5]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: COC1(OC)SC(c2ccncc2)=C(C)NC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1nc(C)c(-c2ccncc2)s1
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
2,2-Dimethoxy-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (200 mg) was dissolved in 2N hydrochloric acid (2 ml), and the mixture was allowed to stand at room temperature for 30 minutes. Then, the solution was made alkaline by addition of 2N aqueous sodium hydroxide under ice-cooling, and the resulting precipitates were collected by filtration. The precipitates were washed with water, air-dried, and was recrystallized from benzene-petroleum ether to give methyl 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylate (158 mg, yield 90%) as colorless needles.
Reaction SMILES: [CH2:1]([S:4][S:5][CH2:6][CH:7]=[CH2:8])[CH:2]=[CH2:3].S([O-])(O[O-])(=O)=[O:10].[K+].[K+]>C(O)C.O>[CH2:3]=[CH:2][CH2:1][S:4](=[O:10])[S:5][CH2:6][CH:7]=[CH2:8]
Reactant: O=S(=O)([O-])O[O-]
Reactant: C=CCSSCC=C
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C=CCSS(=O)CC=C

Procedure:
10 ml of diallyl disulphide (DADS) were stirred into 100 ml ethanol/water (1:1). 20 grams of potassium peroxymonosulfate (Oxone®) was added slowly over 2 hours, and stirred at below 10° C. until no further reaction was observed. The resultant solution was then filtered, and then extracted with diethyl ether (2×50 ml). The diethyl ether layers were combined and washed with 10% brine solution 2×50 ml. The ether layer was dried with magnesium sulfate then reduced to under vacuum. Removal of the solvent produced a yellow oil of pure allicin better than 90% (expressed as a % of pure material). The pure allicin may then be treated as per Example 1 for conversion to ajoene.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[F:11][C:12]1[C:20]([NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])=[CH:19][CH:18]=[C:17]([F:28])[C:13]=1[C:14](O)=[O:15].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:11][C:12]1[C:20]([NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:23])=[O:24])=[CH:19][CH:18]=[C:17]([F:28])[C:13]=1[C:14]([NH:10][C:8]1[CH:9]=[C:4]2[CH:3]=[CH:2][NH:1][C:5]2=[N:6][CH:7]=1)=[O:15]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Reactant: Nc1cnc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
1H-Pyrrolo[2,3-b]pyridin-5-amine (9.97 g, 74.88 mmol), 2,6-difluoro-3-(propylsulfonamido)benzoic acid (23.00 g, 82.37 mmol), EDCI (15.79 g, 82.37 mmol), and HOBt (11.13 g, 82.37 mmol) were charged to a 2 L round-bottomed flask. DMF was added to give a homogeneous solution, and the reaction mixture was stirred at room temperature overnight. The solution was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3×), and the combined organics were washed with water (3×), brine, dried over Na2SO4 and concentrated to a slurry. DCM (500 mL) was added to this slurry, and the mixture was reconcentrated. Additional DCM (500 mL) was added, and the slurry was filtered, washed with DCM and dried under vacuum providing 2,6-difluoro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (15.49 g, 52.5%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 11.65 (br s, 1H), 10.85 (s, 1H), 9.79 (br s, 1H), 8.34-8.37 (m, 2H), 7.51-7.57 (m, 1H), 7.48-7.50 (m, 1H), 6.46-6.48 (m, 1H), 3.11-3.15 (m, 2H), 1.75-1.80 (m, 2H), 0.98-1.02 (m, 3H); m/z (APCI-pos) M+1=395.1.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[NH:16][C:17]([NH:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)=[S:18].[BH4-].[Na+].[NH4+].[Cl-].[NH4+].[OH-]>CO>[CH2:1]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[NH:16][C:17]([NH:19][C:20]1[CH:21]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=1)=[S:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@@H]1CCCC[C@H]1NC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: FC(F)(F)c1cc(NC(=S)N[C@@H]2CCCC[C@H]2NCc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
In the second step, as shown in FIG. 5, benzaldehyde (0.578 mL, 5.45 mmol, 1.05 equiv) was added to a solution of 1-((1R,2R)-2-aminocyclohexyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea (2 g, 5.19 mmol, 1.0 equiv) in anhydrous MeOH (15 mL) under argon at rt. The resulting solution was stirred at rt for 4 hours, then cooled to 0° C. and NaBH4 (211 mg, 5.71 mmol, 1.1 equiv) was added. The reaction mixture was stirred for 20 min and saturated NH4Cl solution (50 mL) was added, followed by NH4OH (2 mL). The resulting mixture was stirred for additional 20 min, then extracted with dichloromethane (100 mL×5), dried over Na2SO4, and evaporated to dryness. The residue was purified by flash chromatography on silica gel using Hexanes/EtOAc/MeOH/NH4OH (400:100:5:1) to afford 1-((1R,2R)-2-(benzylamino)cyclohexyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea (2.02 g, 82% yield) as pale yellow foam. The product was recrystallized from Hexanes/DCM in 75% yield as a white solid. mp 140° C.-141° C.; Rf˜0.48 (DCM/MeOH, 9:1); 1H NMR (CDCl3, 300 MHz) δ=7.69 (s, 2H), 7.48 (s, 1H), 7.29-7.20 (m, 5H), 6.59 (br s, 1H), AB (δ=3.97, 3.82, JAB=12.3 Hz), 3.44 (br s, 1H), 2.49-2.42 (m, 1H), 2.18-2.00 (m, 2H), 1.90-1.75 (m, 2H), 1.40-1.20 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ=183.3, 141.8, 138.0, 131.5 (q, JCF=30 Hz), 129.1, 128.6, 128.3, 128.1, 125.0, 122.4, 121.4, 117.1, 64.4, 62.5, 54.7, 33.2, 32.6, 24.9, 24.6; HRMS (FAB, NBA) Calcd. for C22H24N3SF6 [MH+] m/z 476.1595, found 476.1598.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1.[NH2:31][CH2:32][CH2:33][CH2:34][OH:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:14]=3[N:13]=[C:12]([NH:31][CH2:32][CH2:33][CH2:34][OH:35])[C:11]=2[CH2:10][CH2:9]1
Reactant: NCCCO
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(OCC(F)(F)C(F)(F)F)cccc3c21
Product: Cc1ccccc1N1CCc2c(NCCCO)nc3c(OCC(F)(F)C(F)(F)F)cccc3c21

Procedure:
1-(2-Methylphenyl)-4-chloro-6-β,β,γ,γ,γ-pentafluoropropyloxy-2,3-dihydropyrrolo[3,2-c]quinoline(570 mg, 1.2 mmol) was dissolved in 3-amino-1-propanol(5.0 ml), and reacted at the same condition of Step 6 in the Example 57 to obtain 260 mg of desired compound as solid in 42% of yield.
Reaction SMILES: [OH-].[Na+].CO.[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(OCCCc2ccccc2)cc1NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cc(OCCCc2ccccc2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.090 mL of 2.0 mol/L aqueous sodium hydroxide was added dropwise to a mixed solution of 1 mL of methanol and 1 mL of tetrahydrofuran containing 45 mg of methyl 2-(benzamido)-4-(3-phenylpropoxy)benzoate while ice-cooled and stirred at room temperature for 14 hours and 30 minutes. 0.15 mL of 2.0 mol/L aqueous sodium hydroxide was added dropwise and stirred at the same temperature for 5 hours and 30 minutes. The solvent was evaporated under reduced pressure and water was added and pH was adjusted to pH 4.0 with 1.0 mol/L hydrochloric acid. A solid substance was separated by filtration to obtain 32 mg of 2-(benzamido)-4-(3-phenylpropoxy)benzoic acid as white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:19][NH:18][N:17]=2)[C:10]=1[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:37](I)[CH3:38]>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:28]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:19][N:18]([CH2:37][CH3:38])[N:17]=2)[C:10]=1[F:27])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCI
Reactant: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1-c1n[nH]cc1-c1ccncc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCn1cc(-c2ccncc2)c(-c2c(F)ccc(N(Cc3ccccc3)Cc3ccccc3)c2F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
Dibenzyl[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amine (prepared as described in Example 22) (4 g, 8.84 mmol) was suspended in DCM (44 mL) and 32% NaOH (44 mL) was added followed by tetrabutylammonium bromide (400 mg, 1.24 mmol, 0.14 eq). Neat ethyliodide (1.07 mL, 13.27 mmol, 1.5 eq) was then added and the biphasic mixture was vigorously stirred at room temperature for 1 h. By HPLC analysis at 254 nm the regioisomeric ratio was 55:45 in favour of the most polar N1-substituted pyrazole. The reaction mixture was then diluted with water (50 mL) and DCM (50 mL) and the two layers were separated. Aqueous phase was extracted with DCM (2×50 mL) and combined organic layers were washed with water (2×50 mL) and brine (50 mL), dried over Na2SO4 and evaporated to dryness. The two reagioisomers were separated by flash chromatography on silica gel (n-hexane/ethyl acetate 1:1) and the desired N1-ethylpyrazole was obtained as a white solid in 52% yield.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([C:6]2[NH:10][N:9]=[C:8]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([C:19]4[S:23][C:22]([C:24](=[O:26])[CH3:25])=[CH:21][CH:20]=4)[N:13]=3)[CH:7]=2)[CH2:5][CH2:4]1>C1COCC1.CO>[CH:3]1([C:6]2[NH:10][N:9]=[C:8]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([C:19]4[S:23][C:22]([CH:24]([OH:26])[CH3:25])=[CH:21][CH:20]=4)[N:13]=3)[CH:7]=2)[CH2:5][CH2:4]1
Reactant: CC(=O)c1ccc(-c2ncc(F)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ncc(F)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Reaction time: 1 h
Yield: 86.6 %

Procedure:
NaBH4 (220 mg, 5.82 mmol, 5.0 equiv.) was added to a solution of 1-(5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoropyrimidin-2-yl)thiophen-2-yl)ethanone (Compound 137) (400 mg, 1.17 mmol, 1.0 equiv.) in dry THF (10 mL) and methanol (10 mL) at 0° C. The mixture was stirred for 1 hour, quenched (crashed ice) and concentrated. The residue was recrystallized with methanol and isopropyl ether to give the racemic 1-(5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoropyrimidin-2-yl)thiophen-2-yl)ethanol (350 mg, 87%). LC-MS (m/z)=346.1 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17](O)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:24])=O.CCOC(C)=O>CN(C=O)C>[Cl:24][C:17]1[CH:18]=[CH:19][N:14]([C:11]2[CH:12]=[CH:13][C:6]3[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:8]([CH3:9])[C:7]=3[CH:10]=2)[C:15](=[O:21])[CH:16]=1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(Cl)cc3=O)cc21
Temperature: 47.5 °C
Reaction time: 26 h

Procedure:
To a suspension of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (75 g) in DMF (1.3 L) was added phosphorus oxychloride (29.8 ml) at room temperature, and the mixture was stirred at 45-50° C. under Ar atmosphere for 26 h. The mixture was poured into EtOAc (1.5 L), and washed with saturated NaHCO3 solution (1.5 L). The organic layer was separated, and aqueous layer was extracted with EtOAc (2.0 L) two times. The combined organic layer was washed with brine (1.0 L), dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in EtOAc/THF (1/1, 700 ml), and NH silica gel (100 g) was added to the solution. The mixture was filtered through a plug of NH silica gel (500 g) with EtOAc as an eluent to give the title compound (47.0 g) as a pale yellow solid.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](C1C=CC(O)=CC=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[C:9]([C:1]1[CH:2]=[C:3]([CH3:8])[CH:4]=[CH:5][C:6]=1[OH:7])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Reactant: Cc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(C(C)(C)c2ccccc2)c1
Temperature: 25 °C
Yield: 44.1 %

Procedure:
Paracresol 34.15 g (316.0 mmol), Amberlyst 15E 2.50 g, and toluene 20 ml were charged in a sufficiently dried 200 ml reactor purged with argon, 30 ml of a toluene solution containing 4-cumylphenol 14.40 g (105.5 mmol) was added dropwise to the reactor at 80° C. and then the resultant mixture was stirred for 17 hours. After cooling to a room temperature, the resultant mixture was filtered while being washed with hexane. The obtained liquid was purified by silica gel column chromatography to obtain 2-cumyl-4-methylphenol 10.52 g (44%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].O.[OH-].[Li+].CO>C1COCC1.O>[CH2:18]([C:13]1[C:12](/[CH:11]=[CH:10]/[C:8]2[S:9][C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:22])[N:7]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)OC)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a suspension of 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (150 mg, 0.47 mmol) in THF (1.5 mL) was added a solution of lithium hydroxide monohydrate (39 mg, 0.93 mmol) in water (1.5 mL) followed by methanol (1 mL) and the resulting mixture stirred at room temperature for 1 h. The mixture was then evaporated to half volume and then acidified to pH 4 with HCl (1 N) and cooled to 0° C. for 30 min. A solid precipitated and was filtered off and dried to afford the title compound (130 mg, 91%) which was obtained as a light yellow solid. MS: m/e=305.2 [M−H]−.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[CH:16]=[C:15]1[CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:29])=[O:28])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][O:38][C:39](=[O:50])[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH:48]=O)=[CH:42][CH:41]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][O:38][C:39](=[O:50])[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][C:16]2[C:17]3[C:22](=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:14]([CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:15]=2[CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:29])=[O:28])=[CH:42][CH:41]=1
Reactant: O=S(=O)(Cc1ccccc1)NCCc1cc2ccc(Cl)cc2n1C(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(OCC=O)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3cc(Cl)ccc23)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 35 %

Procedure:
To N-[2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethyl]-C-phenyl-methanesulfonamide (0.033M, 1 equiv.) in DCM at 0° C. were added 4-(2-oxo-ethoxy)-benzoic acid methyl ester (3.3 equiv.), triethylsilane (6 equiv.), and TFA (5 equiv.). The reaction mixture was stirred at rt for 2 d 20 h before aqueous workup. Purification by silica gel chromatography followed by reverse phase HPLC gave 4-{2-[1-Benzhydryl-6-chloro-2-(2-phenylmethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester in 35% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([S:18]([CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)(=[O:20])=[O:19])[CH2:14]1.[ClH:31]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:31].[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([S:18]([CH2:21][CH2:22][NH2:23])(=[O:20])=[O:19])[CH2:14]1
Reactant: COc1ccc2nccc(N3CCC(S(=O)(=O)CCNC(=O)OC(C)(C)C)C3)c2n1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccc2nccc(N3CCC(S(=O)(=O)CCN)C3)c2n1
Reaction time: 2 h

Procedure:
1,1-dimethylethyl [2-({1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-pyrrolidinyl}sulfonyl)ethyl]carbamate (150 mg, 0.34 mmol) was dissolved in a minimum amount of chloroform and treated with 4N HCl in dioxane (2 mL). After stirring 2 h, the reaction mixture was concentrated to dryness and azeotroped with toluene to afford HCl salt of the title compound as a yellow solid which was used without further purification (100 mg, 88%): LC/MS m/z 337 (M+H)+.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[S:21](=[O:23])(=[O:22])[N:20]([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:19](=[O:30])[CH2:18]2)=[C:13]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=1.C(N(CC)CC)C.[CH:46]1([CH2:52][S:53](Cl)(=[O:55])=[O:54])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>C(Cl)Cl>[CH2:32]([O:31][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][NH:8][S:53]([CH2:52][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)(=[O:55])=[O:54])[CH:16]=[CH:15][C:14]=1[N:17]1[CH2:18][C:19](=[O:30])[N:20]([CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[S:21]1(=[O:23])=[O:22])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCN)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=S(=O)(Cl)CC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCNS(=O)(=O)CC3CCCCC3)cc2OCc2ccccc2)S1(=O)=O
Reaction time: 1 h

Procedure:
5-[4-(2-Aminoethyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one TFA salt (Example 67, step A) (0.49 g, 0.96 mmol) is dissolved in 5 mL of CH2Cl2 and triethylamine (0.27 mL, 1.92 mmol) is added. Cyclohexylmethyl sulfonyl chloride (0.19 g, 0.96 mmol) is then added and the reaction stirred for 1 h. The reaction mixture is concentrated and the residue is partitioned between EtOAc and 1N HCl and extracted with EtOAc. The combined organic layers are washed with sat. sodium bicarbonate and brine, dried over MgSO4 and concentrated to a yellow oil. The oil is purified by chromatography over silica (hexane/EtOAc gradient) to afford the title compound as an oil.