Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][C:9]=2[CH2:8][CH2:7][CH2:6][S:5](=[O:19])(=[O:18])[CH2:4]1.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24]Cl>CN(C)C=O>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][N:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C:17]2[CH2:3][CH2:4][S:5](=[O:18])(=[O:19])[CH2:6][CH2:7][CH2:8][C:9]1=2
Reactant: CN(C)CCCCl
Reactant: O=S1(=O)CCCc2[nH]c3ccccc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCn1c2c(c3ccccc31)CCS(=O)(=O)CCC2
Temperature: 90 °C

Procedure:
To a suspension of 2.1g (0.05 mole) of sodium hydride (57% dispersion in mineral oil) in 25 ml of dimethylformamide is added a solution of 12.47g (0.05 mole) of 1,2,4,5,6,7-hexahydrothiocino[5,4-b]indole 3,3-dioxide in 50 ml of dimethylformamide with stirring under nitrogen. The resulting mixture is stirred at 30°-35° C. for one hour. A solution of 6.03g (0.05 mole) of 3-dimethylaminopropyl chloride (freshly distilled) in 25 ml of dimethylformamide is added and the mixture is stirred at room temperature for one hour and then heated in a wax bath at 90° C. for five hours. The dimethylformamide is removed in vacuo. The residue is dissolved in 10% hydrochloric acid and extracted with ether. The aqueous layer is made basic with sodium hydroxide and extracted with ether. The ether layer is washed with water, dried over sodium sulfate and the solvent is removed. Recrystallization from isopropyl ether gives 10.7g (64%) of an analytical sample, m.p. 119°-120° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OC[C@H]2CC[C@H](C)CC2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CC[C@H](COc2cc(F)c(C(=O)O)cc2C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((trans-4-methyl-cyclohexyl)methoxy)benzoate (5.95 g, 16.41 mmol) in anhydrous dichloromethane (28 mL) was added trifluoroacetic acid (14 mL). The mixture was stirred for 1 hour at ambient temperature, and then concentrated in vacuo. The solid was triturated with methanol to give the title compound (2.42 g, 48%):): 1H NMR (300 MHz, CDCl3) δ 12.8 (br s, 1H), 7.30 (d, J=8.5 Hz, 1H), 6.88 (d, J=13.1 Hz, 1H), 3.89 (d, J=6.1 Hz, 2H), 2.05-1.96 (m, 1H), 1.85-1.68 (m, 5H), 1.39-1.25 (m, 1H), 1.17-0.86 (m, 9H), 0.61-0.56 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].[C:14](=O)([O-:35])[O:15][C:16]1C(C)=C(C2C=CC(C3CCCCC3)=CC=2)C=CN=1.[CH:37]1([O:43][C:44]2[CH:49]=[CH:48][C:47](C3C=CN(C([O-])=O)C(=O)C=3C)=[CH:46][CH:45]=2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>O.C1COCC1>[CH:37]1([O:43][C:44]2[CH:49]=[CH:48][C:47]([N:1]([C:14]([O:15][CH3:16])=[O:35])[C@H:2]([C@@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])=[CH:46][CH:45]=2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: Cc1c(-c2ccc(OC3CCCCC3)cc2)ccn(C(=O)[O-])c1=O
Reactant: Cc1c(-c2ccc(C3CCCCC3)cc2)ccnc1OC(=O)[O-]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N(c1ccc(OC2CCCCC2)cc1)[C@@H](C(=O)O)[C@H](C)O
Reaction time: 15 h
Yield: 91 %

Procedure:
To a stirred mixture of D-threonine (0.08 g, 0.67 mmol) and NaHCO3 (0.084 g, 1.0 mmol) in H2O (3.0 mL), the crude mixture containing (4-cyclohexylphenyl)-methyl-2-pyridyl carbonate and [4-(cyclohexoxy)-phenyl]-methyl-2-oxopyridine-1-carboxylate (0.327 g, 1.0 mmol) in THF (3.0 mL) was added. After 15 h at r.t., the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with EtOAc (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.214 g, 91%) as transparent oil, which was used in the next step without further purification. MS (ESI) m/z: 369 [M−NH4]+; (ESI) m/z: 350 [M−H]−. 1H NMR (DMSO-d6): δ 1.08 (d, J=6.3 Hz, 3H), 1.21-1.48 (m, 5H), 1.48-1.57 (m, 1H), 1.66-1.74 (m, 2H), 1.87-1.95 (m, 2H), 3.95 (dd, J=3.4, 9.0 Hz, 1H), 4.06 (dq, J=3.4, 6.3 Hz, 1H), 4.29-4.36 (m, 1H), 6.84 (d, J=9.0 Hz, 1H), 6.91 (d, J=8.3 Hz, 2H), 7.27 (d, J=8.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH:11]([C:13]1[O:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=1)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]([C:4]1[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[NH:6][CH:5]=1)[C:13]1[O:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=1)=[CH:5][NH:6]2
Reactant: Clc1cccc2[nH]ccc12
Reactant: O=Cc1ccc(C(=O)O)o1
Product: O=C(O)c1ccc(C(c2c[nH]c3cccc(Cl)c23)c2c[nH]c3cccc(Cl)c23)o1

Procedure:
The compound Bis(4-chloroindol-3-yl)-(5-carboxy-2-furyl)methane was prepared following procedure A, starting from 4-chloro indole and 5-formyl 2-furan carboxylic acid. LC: Tr 2.31 min, MS: 425 (M+H)+
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][C@@H:17]3[C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:21]4=[CH:20][CH:19]=[C:18]3[C@@H:13]2[CH2:12][CH2:11]1)/[CH:3]=[CH:4]/[C@@H:5]([CH:7]([CH3:9])[CH3:8])[CH3:6].[C:30](OC(=O)C)(=[O:32])[CH3:31].O>N1C=CC=CC=1>[C:30]([O:27][C@H:25]1[CH2:24][CH2:23][C@@:22]2([CH3:28])[C:21](=[CH:20][CH:19]=[C:18]3[C@@H:17]2[CH2:16][CH2:15][C@@:14]2([CH3:29])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[C@H:2]([CH3:1])/[CH:3]=[CH:4]/[C@H:5]([CH3:6])[CH:7]([CH3:8])[CH3:9])[CH2:26]1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)[C@@H](C)/C=C/[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@H](C)/C=C/[C@H](C)C(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of 50 gm (0.13 mol) of ergosterol (1) in 300 mL of anhydrous pyridine was added 33.3 mL (0.35 mol) of acetic anhydride. The mixture was stirred at room temperature overnight and then 600 mL of water was added. The precipitate was filtered and washed three times with 200 mL portions of acetonitrile and then air dried to yield 42.0 g (74%) of (2).
Reaction SMILES: [CH:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C=O.[CH2:12](NCCCC)CCC.C(O)(=O)CCCCCCCCC>>[CH2:12]=[C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:1]=[O:9]
Reactant: CCCCCCCC=O
Reactant: CCCCNCCCC
Agent: C=O
Agent: CCCCCCCCCC(=O)O
Product: C=C(C=O)CCCCCC
Temperature: 95 °C
Yield: 1636.4 %

Procedure:
A 2 L four-necked flask equipped with a stirrer, a thermometer and a reflux condenser was charged with 762 g (6.0 mol) of n-octanal, 520 g (6.4 mol) of a 37% by mass formaldehyde aqueous solution, 15 g (0.33 mol) of dibutyl amine and 10 g (0.06 mol) of decanoic acid, and the contents in the flask were stirred while heating at 95° C. After the elapse of 45 min, it was confirmed that no n-octanal was present in the raw mixture, and then the mixture was cooled and separated into two layers. The thus separated organic layer was subjected to distillation treatment, thereby obtaining 790 g (5.4 mol) of a-methylene octanal (purity as measured by gas chromatography: 95%) (yield based on theoretical amount: 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=O)[C:8](=[O:16])[N:9]2[CH2:12][CH2:13][O:14][CH3:15])=[CH:5][CH:4]=1.[C:18]([NH:26][NH2:27])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6](/[C:7](=[N:27]/[NH:26][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:8](=[O:16])[N:9]2[CH2:12][CH2:13][O:14][CH3:15])=[CH:5][CH:4]=1
Reactant: COCCN1C(=O)C(=O)c2ccc(OC)cc21
Reactant: NNC(=O)c1ccccc1
Product: COCCN1C(=O)/C(=N\NC(=O)c2ccccc2)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 6-methoxy-1-(2-methoxyethyl)-isatin and benzhydrazide according to the synthetic method NMR (CDCl3): δ 3.35 (s, 3H), 3.65 (t, 2H), 3.87 (s, 3H), 3.94 (t, 2H), 6.64 (d, 1H), 7.58 (t, 1H), 7.79 (d, 1H), 13.93 (br s, 1H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]4([OH:36])[CH2:35][CH2:34][S:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])[CH:12]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:41])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2([OH:36])[CH2:31][CH2:32][S:33][CH2:34][CH2:35]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCSCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC2(O)CCSCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.3 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.28 mL, 0.28 mmol) was added to a solution of [5-(4-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-thiopyran-4-ylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 137-(2); 50 mg, 0.09 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature for five hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol=5:2) to give the target compound as a colorless oil (22 mg, 45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=5[F:38])[CH:33]=O)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:50]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)(=[O:52])[CH3:51]>>[C:50]([N:53]1[CH2:58][CH2:57][N:56]([CH2:33][C:32]2[CH:35]=[CH:36][C:37]([F:38])=[C:30]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:39][C:40]6[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=6)[CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:49][CH:48]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)[CH:31]=2)[CH2:55][CH2:54]1)(=[O:52])[CH3:51]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cc(C=O)ccc3F)cn2)cc1
Reactant: CC(=O)N1CCNCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cc(CN4CCN(C(C)=O)CC4)ccc3F)cn2)cc1

Procedure:
In the same manner as Example 1-D-151, using a crude product of 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-benzaldehyde (130 mg) and 1-acetylpiperazine (50 mg) instead of 1-ethylpiperazine, a crude product of 5-{7-[5-(4-acetyl-piperazin-1-ylmethyl)-2-fluoro-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine was obtained as colorless solid (63 mg). Using the crude product (63 mg) of 5-{7-[5-(4-acetyl-piperazin-1-ylmethyl)-2-fluoro-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine, according to the above Deprotection method 2,1-(4-{3-[4-(2-amino-pyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-4-fluoro-benzyl}-piperazin-1-yl)-ethanone was obtained as a colorless powder (30 mg, 70%).
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:41]([OH:43])=[O:42])[CH2:20][S:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:3][CH2:4]C1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:2].[C:44]1([CH3:50])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[C:29]([O:43][C:41](=[O:42])[C@H:19]([CH2:20][S:21][C:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[NH:18][C:1]([O:3][CH2:4][C:48]1[C:49]2[CH2:26][C:25]3[C:50](=[CH:27][CH:28]=[CH:23][CH:24]=3)[C:44]=2[CH:45]=[CH:46][CH:47]=1)=[O:2])([CH3:34])([CH3:30])[CH3:22]
Reactant: Cc1ccccc1
Reactant: O=C(N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Product: CC(C)(C)OC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCc1cccc2c1Cc1ccccc1-2
Temperature: 80 °C

Procedure:
A suspension of Fmoc-S-trityl-L-cysteine (2.9 g, 5 mmol) in dry toluene (10 mL) was heated to 80° C. To this suspension was added over 20 min., di-tert-butyl-dimethylformamide acetal (4.8 mL, 20 mmol). The solution was cooled, washed with water, saturated sodium bicarbonate (2×10 mL), and evaporated. The residue was purified by flash chromatography eluting with ethyl acetate/hexanes (15/85), to give 2.2 g of N-Fluorenylmethoxycarbonyl-S-trityl-L-Cysteine-t-butyl ester.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[C:16]([CH:17]2[CH2:19][CH2:18]2)=[CH:15][CH:14]=[CH:13][C:12]=1[Br:20])(=O)C.O.Cl>CO>[Br:20][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH:17]2[CH2:18][CH2:19]2)[C:11]=1[OH:10]
Reactant: CC(=O)Oc1c(Br)cccc1C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Oc1c(Br)cccc1C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.4 %

Procedure:
Potassium carbonate (276 mg, 2.00 mmol) was added to a solution of 2-bromo-6-cyclopropylphenyl acetate (316 mg, purity: 80%, 1.00 mmol) in methanol (2 ml), and the mixture was stirred at room temperature for 4 hours. After water (15 ml) and 4M hydrochloric acid (15 ml) were added to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was combined, washed with a saturated aqueous NaCl solution, followed by drying with anhydrous sodium sulfate. After the solid was removed by filtration, the filtrate was concentrated to obtain a pale brown oil. This oil was purified by preparative thin layer chromatography (manufactured by Merck Co., Ltd, 1.05744, use of two sheets, development by hexane:ethyl acetate=30:1) to obtain 118 mg of 2-bromo-6-cyclopropylphenol.
Reaction SMILES: [F:1][C:2]1([F:32])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=O)[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:23]=2)[CH:16]=[CH:15][C:14]=1[F:31])[CH3:12].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>O1CCOCC1>[F:1][C:2]1([F:32])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=[S:42])[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:23]=2)[CH:16]=[CH:15][C:14]=1[F:31])[CH3:12]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3cnn(-c4ccc(F)cc4)c3)ccc2F)C1(F)F
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3cnn(-c4ccc(F)cc4)c3)ccc2F)C1(F)F
Yield: 94.5 %

Procedure:
The reaction of (R)-6,6-difluoro-5-{2-fluoro-5-[1-(4-fluoro-phenyl)-1H-pyrazol-4-yl]-phenyl}-5,7,7-trimethyl-[1,4]oxazepan-3-one (189 mg, 422 μmol) with Lawesson's reagent (139 mg, 338 μmol) in 1,4-dioxane (14 ml) yielded the (R)-6,6-difluoro-5-{2-fluoro-5-[1-(4-fluoro-phenyl)-1H-pyrazol-4-yl]-phenyl}-5,7,7-trimethyl-[1,4]oxazepan-3-thione (148 mg, 76% yield) as a white solid. MS (ISP): m/z=464.2.0 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][OH:13])(=[O:3])[CH3:2].N1C=CN=C1.Cl[Si:22]([CH3:28])([CH3:27])[C:23]([CH3:26])([CH3:25])[CH3:24].O>CN(C)C=O>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][O:13][Si:22]([CH3:28])([CH3:27])[C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)OCC=C(C)CCC=C(C)CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCC=C(C)CCC=C(C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
8-Acetoxy-2,6-dimethyl-2,6-octadien-1-ol in dimethylformamide (4 ml) was stirred on an ice bath. To the solution were added imidazole (338 mg, 4.96 mmol) and chlorodimethyl t-butylsilane (410 mg, 2.73 mmol), and the mixture was stirred at room temperature for one hour. After addition of water (30 ml) to the reaction mixture, the product was extracted with hexane (20 mlx2). The extract was dried over MgSO4 and evaporated in vacuo to remove the solvent to give a residue, which was subjected to silica gel column chromatography to obtain 1-acetoxy-8-(dimethyl t-butylsilyl )oxy-3,7-dimethyl-2,6-octadiene (606 mg, 75% ) .
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=2)[C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].P(Cl)(Cl)(Cl)=O.[BH4-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:20][CH2:21][C:22]3[C:27](=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:23]=3)[CH:10]2[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cc1ccc(O)cc1)N(CCc1cccc(OCc2ccccc2)c1)c1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Oc1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(Cl)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 6.8 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-2-(4-hydroxyphenyl)-N-{2-[3-(phenylmethoxy)phenyl]ethyl}acetamide (7.6 g,.0.015 mol) in acetonitrile (30 ml) was added phosphorus oxychloride (4.19 ml, 0.045 mol). The reaction was allowed to reflux at 80° C. for 6 hours. Solvent was removed and the reaction was placed on ice. To the flask was added ice and water. The reaction was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated, and then dissolved in methanol. To the flask was added small aliquots of sodium borohydride (1.02 g, 0.027 mol). The reaction was allowed to stir overnight. The solvent was removed and the reaction was diluted with dichloromethane and water. The organic layer was separated and the aqueous layer was extracted with additional dichloromethane. The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound (0.5 g, 6.8% yield): ES−MS (m/z) 490 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([C:16]([Cl:18])=[O:17])[CH2:9]2.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.O1CCOCC1>CN(C=O)C>[ClH:18].[CH2:36]([NH:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:16]([C@@H:10]3[CH:11]4[CH2:14][CH2:15][N:8]([CH2:13][CH2:12]4)[CH2:9]3)=[O:17])=[CH:25][CH:24]=2)=[CH:27][CH:28]=1)(=[O:34])=[O:33])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1
Reactant: O=C(Cl)[C@H]1CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1)[C@H]1CN2CCC1CC2
Reaction time: 18 h

Procedure:
73.5 mg (0.60 mmol) of potassium carbonate are added to a mixture, prepared under argon, of 74.5 mg (0.35 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 60 mg (0.18 mmol) of 4′-amino-N-benzylbiphenyl-4-sulfonamide (Example 10A) in 2.2 ml of a 10:1 mixture of dioxane and DMF. After 18 h at 100° C., a further 74.5 mg (0.35 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride are added. After a further 24 h at 100° C., the reaction mixture is concentrated in vacuo. The residue is dissolved in water and acetonitrile and purified by preparative HPLC. The product fractions are concentrated, mixed with 5 ml of a 2:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. 64 mg (70.5% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:22].[K+].[K+].O.[OH-].[Na+]>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cl)c2cccc(OCc3ccccc3)c2n1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(O)c2cccc(OCc3ccccc3)c2n1
Temperature: 140 °C
Yield: 80.9 %

Procedure:
To a mixture of 8-(benzyloxy)-4-chloro-2-methylquinoline (3.09 g, 10.9 mmol), potassium carbonate (3.22 g, 32.8 mmol) in DMSO (30 mL) was added water (1.00 mL) to dissolve the solid. The mixture was heated at 140° C. for 2 h and was added 2N NaOH (12 mL, 24.0 mmol) and heated at 130° C. overnight. The mixture was poured into ice/NaHCO3. Solid precipitated and was filtered, washed with water and dried to give 8-(benzyloxy)-2-methylquinolin-4-ol (2.34 g, 81%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)/[C:9](=N/O)/[CH2:8][CH2:7][CH2:6]2)=[CH2:2].[C:15]([O:22][CH2:23]C)(=[O:21])[C:16]([O:18]CC)=O.C[O-:26].[Na+]>CO>[O:18]=[C:16]([CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH:1]=[CH2:2])[CH:4]=2)[C:9]1=[O:26])[C:15]([O:22][CH3:23])=[O:21]
Reactant: C=Cc1ccc2c(c1)CCC/C2=N\O
Reactant: C[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na+]
Solvent: CO
Product: C=Cc1ccc2c(c1)CCC(C(=O)C(=O)OC)C2=O

Procedure:
To a 250 mL round bottom flask charged with a solution of 6-vinyl-3,4-dihydronaphthalen-1(2H)-one (intermediate 1, 400 mg, 2.323 mmol) and diethyl oxalate (0.630 mL, 4.65 mmol) in methanol (20 mL) was added sodium methoxide (25% wt in MeOH) (2008 mg, 9.29 mmol) via syringe. After the addition was complete, the dark reaction mixture was heated at reflux for 10 h. The reaction was quenched with 50% HCl aq. solution and then evaporated to remove the methanol. The aqueous residue was diluted with water (80 mL) and extracted with dichloromethane (2×100 ml). The organic layers were combined, concentrated, and purified by silica gel chromatography, (40 g Isco column, 0% to 25% ethyl acetate in hexane gradient) to yield the title compound. The compound had an HPLC ret. time=1.05/2.0 min. (condition E); MS:(M+H)=259.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[Cl-].[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C:25](O)=[O:26])[CH3:21]>O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:25](=[O:26])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:28])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)Nc1ccc(N)c([N+](=O)[O-])c1

Procedure:
7.65 gm (0.05 mol) of 1,4-diamino-2-nitrobenzene were added to 80 ml of absolute tetrahydrofuran and 5.1 gm (0.05 mol) of triethylamine at room temperature to form a solution. While this mixture was being stirred, 7.5 gm (0.05 mol) of malonic acid monoethylester chloride were added dropwise thereto. After termination of the addition, the mixture was stirred at room temperature for another 6 hours. Then the solvent was evaporated in vacuo for the most part. The residue was suctioned off and recrystallized once from ethanol/activated charcoal and a second time from water. The product had a melting point of 133°-136°C.