Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]([CH2:30][CH:31]([OH:33])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:41]([N:51]([CH2:53][C:54](O)=[O:55])[CH3:52])([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:44]([O:43][C:41]([N:51]([CH3:52])[CH2:53][C:54]([O:33][C@H:31]([CH3:32])[CH2:30][N:27]1[C:28]([CH3:29])=[C:24]([C:22](=[O:23])[NH:21][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[C:2]([F:1])[CH:3]=2)[C:25](=[O:40])[N:26]1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:55])=[O:42])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CC(C)O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)CN(C)C(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a mixture of (R)—N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)-phenyl-1-(2-hydroxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (2.0 g, 3.68 mmol), N-Cbz-sarcosine (1.643 g, 7.36 mmol) and DMAP (0.9 g, 7.36 mmol, Aladdin) in 15 mL of CH2Cl2 was added EDC solid (1.06 g, 5.52 mmol, Aladdin) in portions at 0° C. After stirring at 0° C. for 2 hrs, the reaction mixture was warmed up to room temperature, and continued to stir at rt overnight. The mixture was diluted with 100 mL of CH2Cl2 and the resulted solution was washed with 0.1 N HCl (10 mL×2), followed by saturated NaHCO3 solution (20 mL×2) and water (20 mL). The aqueous phase was extracted with EtOAc (50 mL×3), and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/hexane=2/1) to give the desired compound as a pale yellow solid (2.31 g, 84%).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:2]#[CH:3].[C:10]([C:14]1([CH2:18]O)[CH2:17][O:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]12[CH2:15][O:16][C:7]([CH2:6][CH2:5][O:4][CH2:1][C:2]#[CH:3])([O:9][CH2:18]1)[O:8][CH2:17]2)([CH3:13])([CH3:12])[CH3:11]
Reactant: C#CCOCCC(=O)O
Reactant: CC(C)(C)C1(CO)COC1
Product: C#CCOCCC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
4-t-Butyl-1-[2-(prop-2-ynyloxy)ethyl]-2,6,7-trioxabicyclo[2.2,2]octane was prepared from 3-(prop-2-ynyloxy)propionic acid and 3-t-butyl-3hydroxymethyloxetane using methodology described in Example I.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([N:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][C@H:30]2[CH3:42])[C:12]2[CH2:18][N:17]([C:19]3[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=3[CH3:28])[CH2:16][CH2:15][C:13]=2[N:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[CH3:42])[C:12]2[CH2:18][N:17]([C:19]3[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=3[CH3:28])[CH2:16][CH2:15][C:13]=2[N:14]=1
Reactant: Cc1ccc(C)c(-c2nc3c(c(N4CCN(C(=O)OC(C)(C)C)C[C@H]4C)n2)CN(c2cc(C(C)C)ccc2C)CC3)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C)c(-c2nc3c(c(N4CCNC[C@H]4C)n2)CN(c2cc(C(C)C)ccc2C)CC3)c1

Procedure:
(R)-tert-Butyl 4-(2-(2,5-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (60 mg, 0.105 mmol) in DCM (1 mL) was treated with TFA (1 mL, 13.0 mmol) at rt for 15 min. The mixture was then concentrated to provide (R)-2-(2,5-Dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-4-(2-methylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, which was taken on without need further purification. MS (ESI+) m/z 470.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]2[NH:27][N:26]=[N:25][N:24]=2)[CH:20]=[CH:21][CH:22]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[NH:27][N:26]=[N:25][N:24]=4)[CH:18]=3)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: Cc1c(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)sc2ccc(F)cc12
Yield: 36 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 5-fluoro-3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 14) (26 mg, 0.10 mmol) and 5-(3-amino-phenyl)tetrazole (31 mg, 0.19 mmol). The title compound was obtained in 36% yield (13.9 mg). MS (ESI+) calcd for C16H12FN5O2S2 389.041644, found 389.042334.
Reaction SMILES: O=[CH:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH2:19][C:20]1([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[C:8]([O:7][C:6]([NH:5][CH2:4][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][NH:19][C:20]1([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:12])([CH3:11])([CH3:10])[CH3:9]
Reactant: COC(=O)C1(N)CCCC1
Reactant: CC(C)(C)OC(=O)NCC(C=O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(NCC(CNC(=O)OC(C)(C)C)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a solution of tert-butyl (3-oxo-2-phenylpropyl)carbamate from Step B (0.5 g, 2 mmol) in dry chloroform (20 mL) was added methyl 1-amino-1-cyclopentanecarboxylate (0.431 g, 3.01 mmol). After 15 minutes, sodium triacetoxyborohydride (0.893 g, 4.21 mmol) was added. After 4 hours of stirring at ambient temperature, the reaction mixture was diluted with DCM and 5% sodium bicarbonate. The layers were separated and the aqueous layer was extracted once with DCM. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to yield a residue, which was subjected to a normal phase chromatography, eluting with a gradient of 1-6% methanol in DCM. Concentration of the fractions containing the product provided the title compound. MS: m/z=377 (M+1).
Reaction SMILES: [CH2:1]([C@@H:4]1[S:9](=[O:11])(=[O:10])[C:8]([CH3:13])([CH3:12])[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6][C@@:5]1([C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[F:32])[CH3:22])[CH:2]=C.C(=O)(O)[O-:34].[Na+].O=O.[BH4-].[Na+]>C(Cl)Cl.CO>[F:32][C:24]1[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:23]=1[C@:5]1([CH3:22])[C@H:4]([CH2:1][CH2:2][OH:34])[S:9](=[O:11])(=[O:10])[C:8]([CH3:13])([CH3:12])[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6]1
Reactant: O=C([O-])O
Reactant: C=CC[C@H]1[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C(NC(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Agent: O=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)[C@H](CCO)S(=O)(=O)C1(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl ((5R,6S)-6-allyl-5-(2-fluoro-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (250 mg, 0.532 mmol) (cis-isomer from Step 1) in DCM (4 ml) and MeOH (1.3 ml), was added sodium bicarbonate (89 mg, 1.065 mmol) and the mixture was cooled to −78° C. The resulting mixture was ozonolized for about 10 min or until analysis showed no starting material present. The stream of oxygen was passed through the solution for 5 min, then solid sodium borohydride (40.3 mg, 1.065 mmol) was added to the mixture. The flask was removed from the bath and allowed to reach RT and stirred for 30 min. The reaction was quenched with saturated NH4Cl solution (caution: there is evolution of gas), diluted with water to dissolve solids and extracted into EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to afford tert-butyl ((5R,6S)-5-(2-fluoro-5-nitrophenyl)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate which was used in the next step without further purification.
Reaction SMILES: OP([O-])(O)=O.[K+].[O-]S([O-])(=O)=O.[Mg+2].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.Cl.Cl.[C:27]([NH:35][CH2:36][CH2:37][O:38][C:39]([C:41]1[CH:46]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([N+:53]([O-:55])=[O:54])[CH:48]=2)[C:45]([C:56]([O:58]CCNC(=O)C2C=CC=NC=2)=[O:57])=[C:44]([CH3:70])[NH:43][C:42]=1[CH3:71])=[O:40])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1>O>[CH3:71][C:42]1[NH:43][C:44]([CH3:70])=[C:45]([C:56]([OH:58])=[O:57])[C@@H:46]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([N+:53]([O-:55])=[O:54])[CH:48]=2)[C:41]=1[C:39]([O:38][CH2:37][CH2:36][NH:35][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1)=[O:40]
Reactant: CC1=C(C(=O)OCCNC(=O)c2cccnc2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCCNC(=O)c2cccnc2)=C(C)N1
Agent: Cl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Solvent: O
Product: CC1=C(C(=O)O)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCCNC(=O)c2cccnc2)=C(C)N1
Reaction time: 72 h
Yield: 24.6 %

Procedure:
Paecilomyces sp. FI-1007 was inoculated on 30 ml medium FI (2% potato starch, 2% ESUSAN Meat, 0.1% KH2PO4, 0.05% MgSO4 7H2O, 1% glucose, 0.05% Adekanol LG109) charged in an Erlenmeyer flask of 250 ml volume. Incubation was performed at 28° C. for 3 days. A solution of 60 mg of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid bis(2-nicotinoylaminoethyl)ester dihydrochloride in 0.75 ml of distilled water was added to the culture broth obtained. Shaking was continued for further 2 days at 28° C. Thereafter the culture broth was treated in a manner similar to Example 1-1) to give 10 mg of the title compound in an optical purity of 100%.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][CH:8]([OH:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)(C)(C)C>C1(C)C=CC=CC=1>[OH:18][CH:8]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=1)[CH2:7][C:6]([OH:19])=[O:5]
Reactant: CC(C)(C)OC(=O)CC(O)CCc1ccc(I)cc1
Solvent: Cc1ccccc1
Product: O=C(O)CC(O)CCc1ccc(I)cc1
Temperature: 25 °C
Yield: 57.2 %

Procedure:
Silica gel (19 g) was added to a stirred solution of 3-hydroxy-5-(4-iodo-phenyl)-pentanoic acid tert-butyl ester (Intermediate 9, 1.2 g, 3.2 mmol) in toluene (100 mL) and the resulting suspension heated at reflux for 5.5 hours. The reaction was cooled to room temperature and then filtered through a thin pad of celite, washing with 20% methanol/dichloromethane (2×50 mL). The filtrate was evaporated under reduced pressure to give the title compound (586mg, 57%) as a white solid. LC/MS: 3.01 min; z/e 319, calcd (M−1) 319. 1H NMR (400 MHz: DMSO-d6): 7.63 (2 H), 7.00 (2 H), 3.77 (1 H), 2.60 (2 H), 2.3 (2 H), 1.62 (2 H).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]2[CH:25]=[CH:24][C:18]3=[N:19][CH:20]=[C:21](Cl)[CH:22]=[C:17]3[C:16](=[O:26])[C:15]=2[CH:27]=1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]2[CH:25]=[CH:24][C:18]3=[N:19][CH:20]=[C:21]([C:32]4[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=4)[CH:22]=[C:17]3[C:16](=[O:26])[C:15]=2[CH:27]=1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(O[Si](C)(C)C(C)(C)C)c1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A test tube fitted with a teflon septum was charged with 7-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (50 mg, 0.13 mmol), PdCl2(PPh3)2 (9 mg, 0.013 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (78 mg, 0.38 mmol), and sodium carbonate (40 mg, 0.38 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed dioxane (1.2 mL) was added and the mixture was stirred at 100° C. overnight. The solution was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, concentrated in vacuo, and purified via flash chromatography (silica, 20-100% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 8.99 (d, 1H); 8.58 (d, 1H); 8.19 (d, 1H); 7.90 (d, 1H); 7.97 (s, 1H); 7.72 (dd, 1H); 7.56 (d, 1H); 7.32 (d, 1H); 7.22 (d, 1H); 5.01 (q, 1H); 3.97 (s, 3H); 1.44 (d, 3H); 0.90 (s, 9H); 0.06 (s, 3H); −0.02 (s, 3H). LRMS (APCI) calc'd for (C26H32N3O2Si) [M+H]+, 446.2; found, 446.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:10](#[N:13])[CH:11]=[CH2:12].C(N(CC)C(C)C)(C)C>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:12][CH2:11][C:10]#[N:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: C=CC#N
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OCCC#N)cc1

Procedure:
That is, 4-methoxyphenol (a) is reacted with acrylonitrile (b) in the presence of a base such as Triton B, triethylamine, N,N-diisopropylethylamine or the like, at 25 to 120° C. for 1 to 72 hours to obtain 3-(4-methoxyphenoxy)propionitrile (c), and the resultant is either reduced in a solvent such as tetrahydrofuran, dioxane or the like at 25 to 100° C. using a borane-tetrahydrofuran complex, a borane-dimethylsulfide complex, lithium aluminum hydride or the like, or reduced in a hydrogen atmosphere or in the presence of ammonia, using a catalyst such as Raney nickel or the like, thus to obtain 3-(4-methoxyphenoxy)propylamine (d). Subsequently, the resultant is reacted with 3-hydroxybenzaldehyde (e) in a solvent such as methanol, ethanol, isopropyl alcohol, tetrahydrofuran, toluene, acetonitrile or the like, and then the resultant is reduced using a reducing agent such as sodium borohydride, sodium triacetoxy borohydride or the like to obtain N-(3-(4-methoxyphenoxy)propyl)-3-hydroxybenzylamine (f). This is reacted with 2-chlorobenzoxazole (g) in a solvent such as dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, ethyl acetate or the like, in the presence of an inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate or the like, or an organic base such as triethylamine, N,N-diisopropylethylamine, pyridine or the like, thus to obtain N-(benzoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)-3-hydrox ybenzylamine (compound (2)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[O:5][C:6]1[S:27][C:9]2[N:10]([CH3:26])[C:11](=[O:25])[N:12]([CH2:15][CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C:13](=[O:14])[C:8]=2[C:7]=1[CH:28]=[O:29].[Cl:33][C:34]1[CH:35]=[C:36]([Mg]Br)[CH:37]=[CH:38][CH:39]=1>C1COCC1.CC(=O)OCC.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[O:5][C:6]1[S:27][C:9]2[N:10]([CH3:26])[C:11](=[O:25])[N:12]([CH2:15][CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C:13](=[O:14])[C:8]=2[C:7]=1[CH:28]([C:37]1[CH:36]=[CH:35][C:34]([Cl:33])=[CH:39][CH:38]=1)[OH:29]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Oc3cccc(Cl)c3)sc21
Reactant: Clc1cccc([Mg]Br)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cccc(Cl)c3)sc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
To a solution of 6-(3-chlorophenoxy)-1-methyl-2,4-dioxo-3-(3-(tetrahydro-2H-pyran-2-yloxy) propyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (65 mg, 0.136 mmol) in THF (2 mL) was added (3-chlorophenyl)magnesium bromide (35 mg, 0.163 mmol). The reaction was stirred at RT for 15 minutes then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to give a residue which was purified by chromatography eluted with PE/EA (4:1) to give 6-(3-chlorophenoxy)-5-((4-chlorophenyl) (hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (45 mg, 56.3% yield) as a yellow oil. LCMS: MH+ 591 and TR=2.138 min.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:35]I>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][I:35])=[CH:6][N:7]=1
Reactant: OCCc1ccc(Br)nc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Brc1ccc(CCI)cn1
Reaction time: 6 h
Yield: 91.6 %

Procedure:
A solution of 2-(6-bromopyridin-3-yl)ethanol (2.0 g, 9.9 mmol, 1.0 equiv) in dichloromethane (31 mL) was added dropwise to a solution of imidazole (0.91 g, 13.4 mmol, 1.4 equiv), triphenylphosphine (3.3 g, 12.4 mmol, 1.3 equiv), and iodine (3.1 g, 12.4 mmol, 1.3 equiv) in dichloromethane (31 mL) at room temperature. After stirring for 6 h, the reaction was filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (15% ethyl acetate in heptane) to provide the title compound as a white solid (2.83 g, 92%). MS (LCMS) m/z 312.0 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 3.15 (t, J=7.03 Hz, 2H) 3.43 (t, J=7.03 Hz, 2H) 7.54 (d, J=7.81 Hz, 1H) 7.61 (dd, J=8.20, 2.73 Hz, 1H) 8.22 (d, J=2.34 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:25]1[CH:29]=[CH:28][C:27]([C:30]2[S:34][CH:33]=[C:32]([S:35](Cl)(=[O:37])=[O:36])[CH:31]=2)=[N:26]1.C(N(CC)CC)C>>[O:25]1[CH:29]=[CH:28][C:27]([C:30]2[S:34][CH:33]=[C:32]([S:35]([N:22]3[CH2:23][CH2:24][CH:19]([C:10]4[C:9]5[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]6[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=6)[CH:8]=5)[NH:12][CH:11]=4)[CH2:20][CH2:21]3)(=[O:37])=[O:36])[CH:31]=2)=[N:26]1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: O=S(=O)(Cl)c1csc(-c2ccon2)c1
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)c4csc(-c5ccon5)c4)CC3)c[nH]c12

Procedure:
Following the general procedure in example 267, 5-(phenyl)-3-(4-piperidinyl)-1H-indole-7-carboxamide (32 mg, 0.1 mmol), 5-(3-isoxazolyl)-3-thiophenesulfonyl chloride (37.5 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.3 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (11.7 mg, 22%).
Reaction SMILES: C1(OC([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C(C)C)[CH:17]=3)[CH2:12][CH2:11]2)=O)C=CC=CC=1.C(O)(=O)C.O>Br>[NH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1
Reactant: CC(C)Oc1cccc(C2CCN(C(=O)Oc3ccccc3)CC2)c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Oc1cccc(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
4-(3-(1-Methylethoxy)phenyl)-1-piperidine-carboxylic acid phenyl ester (Preparation 46, 1.7 g, 5.01 mmol) was heated under reflux in 47% aqueous hydrobromic acid:glacial acetic acid (1:1, 20 ml) for 16 h. The solution was allowed to cool to room temperature and water (10 ml) was added. The solution was extracted with methyl tert-butyl ether (3×10 ml) to remove phenol as a by-product. The pH was adjusted to 10.3-10.5 with 15% w:v aqueous sodium hydroxide solution and the reaction mixture was left at room temperature for 2 h to precipitate the product. After cooling to 0° C. the precipitate was filtered and washed with cold water (5 ml) to give the title compound as a solid (380 mg, 43%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CS(O[CH2:24][C:25]1([CH2:28][N:29]2[C:34](=[O:35])[C:33]([CH3:36])=[CH:32][N:31]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:30]2=[O:44])[CH2:27][CH2:26]1)(=O)=O>>[CH2:37]([N:31]1[CH:32]=[C:33]([CH3:36])[C:34](=[O:35])[N:29]([CH2:28][C:25]2([CH2:24][N:14]3[CH2:15][CH2:16][N:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][C:2]([F:1])([F:17])[F:18])[CH2:12][CH2:13]3)[CH2:27][CH2:26]2)[C:30]1=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Cc1cn(Cc2ccccc2)c(=O)n(CC2(COS(C)(=O)=O)CC2)c1=O
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Product: Cc1cn(Cc2ccccc2)c(=O)n(CC2(CN3CCN(c4ccccc4OCC(F)(F)F)CC3)CC2)c1=O

Procedure:
substituting 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 1-(1-benzyl-5-methyl-2,4-dioxo-(1H,3H)-pyrimidin-3-ylmethyl)cycloprop-1-ylmethyl methanesulfonate gave 1-benzyl-3-(1-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-ylmethyl}cycloprop-1-ylmethyl)-5-methyl-2,4(1H,3H)-pyrimidinedione as an oil;
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:16](=[O:17])[CH2:15][N:14]([CH2:12][CH3:13])[C:10]1=[S:11]
Reactant: Cc1cccc(N=C=S)c1C
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(c2cccc(C)c2C)C1=S
Yield: 41.5 %

Procedure:
The title compound was prepared by the procedure described in Example 9 using 16.3 g of 2,3-dimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethanol afforded the title compound (10.3 g) as a light pink solid, m.p. 120°-121° C. Anal. Calcd. for. C13H16N2OS: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.72; H, 6.44; N, 11.47. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.CS(CCC[N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=O)=O>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31]([N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)=[O:32])[C@H:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNCC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C37H47N4O4SCl2 [(M+H)+] 713.2690, observed 713.2687.