Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[O:12][CH2:11][CH2:10][C:9]([C:13](Cl)=[O:14])=[CH:8][C:7]=2[CH:16]=1.[CH3:19][O:20][CH2:21][CH:22]1[NH:27][CH2:26][CH2:25][N:24]([C:28](=[O:41])[C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)[CH2:23]1.Cl.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[O:12][CH2:11][CH2:10][C:9]([C:13]([N:27]3[CH2:26][CH2:25][N:24]([C:28](=[O:41])[C:29]4[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=4)[CH2:23][CH:22]3[CH2:21][O:20][CH3:19])=[O:14])=[CH:8][C:7]=2[CH:16]=1
Reactant: COc1cc2c(cc1OC)OCCC(C(=O)Cl)=C2
Reactant: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)C1=Cc2cc(OC)c(OC)cc2OCC1
Reaction time: 0.5 h

Procedure:
A solution of 7,8-dimethoxy-2,3-dihydro-1-benzoxepine-4-carbonyl chloride (300 mg) in dichloromethane (10 ml) is added dropwise, taking 30 minutes under ice-cooling while stirring, to a mixture of 3-methoxymethyl-1-(3,4,5-trimethoxybenzoyl)piperazine×hydrochloride (400 mg) obtained in Reference Example 6, triethylamine (1 ml) and dichloromethane (30 ml). The reaction mixture is washed with an aqueous solution of citric acid and an aqueous solution of sodium hydrogencarbonate, then dried over magnesium sulfate, followed by concentration. The concentrate is subjected to a silica gel column chromatography (eluent: ethyl acetate-methanol =95:5) to afford 1-(7,8-dimethoxy2,3-dihydro-1-benzoxepin-4-ylcarbonyl) -2-methoxymethyl4-(3,4,5-trimethoxybenzoyl)piperazine (520 mg) as colorless crystals, m.p. 142° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.[C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)(=[O:18])[CH3:17]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:17]/[C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:18])=[CH:5][C:4]=1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(C=O)cc1-c1cccs1
Product: COc1ccc(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1
Yield: 71 %

Procedure:
The title compound was prepared by condensing 4-methoxy-3-(thiophen-2-yl)-benzaldehyde (Ex-41A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 219–220° C., 71% yield. 1H-NMR (DMSO-D6) δ 13.36 (br s, 1H), 8.25–8.31 (m, 3H), 8.11 (d, J=8 Hz, 2H), 7.85–7.98 (m, 3H), 7.78–7.80 (m, 1H), 7.61 (d, J=5 Hz, 1H), 7.25 (d, J=9 Hz, 1H), 7.17 (dd, J=4, 6 Hz, 1H), 3.99 (s, 3H). HRMS m/z=calc. 365.0848, found 365.0833.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH2:20][O:21][C:22]3[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:23]=3[CH3:31])=[C:18]([CH3:32])[N:17]=[C:16]([Cl:33])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>C(Cl)Cl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[Cl:33][C:16]1[N:17]=[C:18]([CH3:32])[C:19]([CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH:28]([CH3:29])[CH3:30])[CH:25]=[CH:24][C:23]=2[CH3:31])=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[N:15]=1
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCNCC1
Reaction time: 0.33 h

Procedure:
To a solution of 4-[2-chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.05 mmol) in DCM (5 mL) is added trifluoroacetic acid (1 mL) with magnetic stirring. Gas evolution is observed and continues for ˜20 min. The light yellow colored solution is evaporated at reduced pressure, diluted with DCM (20 mL) and evaporated again. Placed under high vacuum (˜0.2 Torr) for 20 min to obtain the title compound as a colorless oil. LC/MS (Method 2), M+H=432.1, Rt=1.46 min.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH:15][C@:16]([CH3:52])([CH2:50][OH:51])[C:17](=[O:49])[C@@H:18]([NH:26][C:27](=[O:48])[C@@H:28]([NH:32][C:33](=[O:47])[C@@H:34]([NH:38][C:39]([C:41]1[S:45][C:44]([CH3:46])=[N:43][CH:42]=1)=[O:40])[CH2:35][O:36][CH3:37])[CH2:29][O:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:51][CH2:50][C@:16]([OH:15])([CH3:52])[C:17](=[O:49])[C@@H:18]([NH:26][C:27](=[O:48])[C@@H:28]([NH:32][C:33](=[O:47])[C@@H:34]([NH:38][C:39]([C:41]2[S:45][C:44]([CH3:46])=[N:43][CH:42]=2)=[O:40])[CH2:35][O:36][CH3:37])[CH2:29][O:30][CH3:31])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)COS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
4-(Trifluoromethyl)benzenesulfonyl chloride (0.71 g, 2.89 mmol) in DCM (5 mL) was added dropwise to N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide (1.59 g, 0.00289 mol), DMAP (0.1 g) and DIEA (0.60 mL, 3.47 mmol) in DCM (15 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred overnight. The mixture was washed with 2N aqueous HCl, brine, dried (MgSO4) and evaporated. The residue was purified by Biotage flash column chromatography (5% MeOH/25% EtOAc, DCM) to give product as a white solid (1.1 g, 52%); 1H NMR (CDCl3): δ 8.08-8.03 (m, 3H), 7.82 (d, J=8.4 Hz, 2H), 7.32 (d, J=7.6 Hz, 1H), 7.28-7.15 (m, 5H), 7.02 (d, J=8.4 Hz, 1H), 6.94 (d, J=6.8 Hz, 1H), 5.40-5.32 (m, 1H), 4.76-4.72 (m, 1H), 4.58-4.52 (m, 1H), 4.30 (d, J=9.2 Hz, 1H), 3.86-3.80 (m, 3H), 3.63-3.59 (m, 1H), 3.50-3.36 (m, 7H), 3.12-3.06 (m, 1H), 2.95-2.90 (m, 1H), 2.70 (s, 3H), 0.74 (s, 3H); MS for C32H37F3N4O10S2 m/z: 759 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[CH:4][CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.CS(O)(=O)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[CH:11]=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: Brc1ccc(-c2nnc[nH]2)cc1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: Brc1ccc(-c2nncn2C2CCCCO2)cc1
Yield: 248.3 %

Procedure:
A solution of 3-(4-Bromophenyl)-4H-1,2,4-triazole (14.1 g, 62.9 mmol), 3,4-dihydro-2H-pyran (10.59 mmol) and methanesulfonic acid (1.19 g, 6.29 mmol) in tetrahydrofuran (150 mL) was heated at 75° C. for 2 h. The solution was condensed and partitioned between sodium bicarbonate solution and ethyl acetate (3×), the organics dried over magnesium sulfate, filtered and solvent removed under reduced pressure. The solid was triturated with 10% ethyl acetate in hexanes to afford the title compound (8.1 g, 26.3 mmol, 70% yield). MS (ESI) m/z 308.4 [M]+, 310.5 [M+2]+.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[CH:4][C:3]=1[C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[CH3:19][O:20][NH2:21].N1C=CC=CC=1>CCO>[CH3:19][O:20][N:21]=[C:11]([C:3]1[CH:4]=[C:5]([C:9]#[N:10])[C:6](=[O:8])[NH:7][C:2]=1[CH3:1])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CON
Reactant: CCCCCC(=O)c1cc(C#N)c(=O)[nH]c1C
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCCC(=NOC)c1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C

Procedure:
A mixture of 1,2-dihydro-6-methyl-2-oxo-5-(1-oxohexyl)-3-pyridinecarbonitrile (0.80 g, 0.0034 mol), methoxyamine hydrochloride (0.32 g, 0.0038 mol) and pyridine (2.0 ml) were heated and stirred at reflux overnight in EtOH (30.0 ml). The solution was allowed to cool to room temperature and the solvent was removed on the rotary evaporator. The pasty residue was triturated with H2O, filtered and recrystallized (EtOH-H2O) giving 0.5 g (56%) m.pt. 159°-165° C. One more recrystallization gave the analytical sample m.pt. 170°-171° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[C:23]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([NH:32][CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1
Reactant: NCCCc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCCCc2ccccc2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo [1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and 3-phenylpropylamine in DME. ES-MS m/e (%): 374 (M+H+, 100).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.[O:8]=[S:9]1(=[O:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F>CS(C)=O.O>[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[N:12]1[CH2:13][CH2:14][S:9](=[O:15])(=[O:8])[CH2:10][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: O=S1(=O)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCS(=O)(=O)CC2)c(F)c1
Temperature: 100 °C
Yield: 110.1 %

Procedure:
To a suspension of K2CO3 (5.53 g, 40 mmol) and 1,1-dioxo-thio-morpholinehydrochloride (3.60 g, 21 mmol) in DMSO (50 mL) was added 3,4-difluoronitrobenzene (3.18 g, 20 mmol). The reaction was heated at 100° C. for 12 h. The mixture was diluted with water (150 mL) and extracted with CH2Cl2 (100 mL×2). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow solid (6.04 g, 70%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([C:40]([OH:42])=[O:41])[CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:39][CH2:38][CH2:37][C@H:36]([C:40]([OH:42])=[O:41])[CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)[C@H]1CCCNC1
Product: O=C1N=C(N2CCC[C@H](C(=O)O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-3-(S)-carboxylic acid was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperidine-3-(S)-carboxylic acid following General Procedure C.
Reaction SMILES: [CH2:1]([CH:8]1[O:22][C:12]2=[CH:13][C:14]3[C:18]([CH:19]=[C:11]2[C:10](=O)[C:9]1=[O:24])=[N:17][C:16]([CH3:21])([CH3:20])[CH:15]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CN(C=O)C.O.NN>[CH2:1]([CH:8]1[O:22][C:12]2=[CH:13][C:14]3[C:18](=[CH:19][C:11]2=[CH:10][C:9]1=[O:24])[NH:17][C:16]([CH3:21])([CH3:20])[CH:15]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)C=c2cc3c(cc2=N1)C(=O)C(=O)C(Cc1ccccc1)O3
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C=c2cc3c(cc2N1)=CC(=O)C(Cc1ccccc1)O3
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
To a solution of 6-Benzyl-2,2-dimethyl-2H-pyrano[2,3-f]indole-7,8-dione (500 mg, 1.57 mmol) in DMF (5 mL), hydrazine monohydrate (2.5 mL) was added, and the resulting mixture was stirred at 100° C. for 1.5 hour. Water was added thereto, and the resulting solution was extracted with ethyl acetate. The resulting organic phase was washed with saturated aqueous ammonium chloride solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column (hexane/ethyl acetate=3/1) to obtain the aimed product (yield: 65%).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4]>CO>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C:2]([CH3:17])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1
Reactant: COC(=O)C(C)(C)Cc1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: COC(=O)C(C)(C)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound (i) (736 mg, 3.06 mmol) was dissolved in MeOH (15 mL) at RT and this solution degassed with N2. Palladium on carbon (10%) (25 mg) was suspended in water/MeOH (0.5 mL/2 mL) and added to the substrate solution. The mixture was again degassed with N2 and then vacuum/flushed with H2. The mixture was stirred under a H2 balloon overnight at RT. The mixture was filtered through celite, washed with MeOH and the filtrate evaporated to dryness to afford a clear oil which was placed under high vacuum for 1 h to afford the desired product (ii), 620 mg. 1H NMR (400 MHz, CDCl3) δ 6.88 (d, J=8.3 Hz, 2H), 6.60 (d, J=8.3 Hz, 2H), 3.64 (s, 3H), 2.74 (s, 2H), 1.15 (s, 6H).
Reaction SMILES: C1(CC([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[C:17]3[CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=3[O:31][CH3:32])=[CH:12][CH:11]=2)=O)CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>C(OCC)(=O)C>[NH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(NC(=O)CC4CCCC4)cc23)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cc2cccc3ccc(N)cc23)c(OC)c1
Yield: 90.9 %

Procedure:
A mixture of methyl 4-[7-(cyclopentylacetamido)naphth-1-ylmethyl]-3-methoxybenzoate (15.00 g), anhydrous p-toluenesulfonic acid (11.97 g), and methanol (dried over 3A molecular sieves) (70 ml) was refluxed for 42 hours. After cooling, the mixture was added to ethyl acetate (250 ml), washed (saturated sodium bicarbonate, brine), dried (MgSO4) and evaporated. The solid obtained was recrystallized from 1:12 methanol:methylene chloride and petroleum ether to give methyl 4-(7-aminonaphth-1-ylmethyl)-3-methoxybenzoate (10.15 g, 91%) as a light tan solid; mp 138°-40° C., MS(CI), m/e=322(M+H).
Reaction SMILES: O[C@@H:2]([CH3:12])[CH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:12][C@@H:2]1[CH2:3][C:4]2[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=2[O:11]1
Reactant: Cc1ccc(O)c(C[C@H](C)O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C[C@@H](C)O2

Procedure:
To a mixture of (S)-2-(2-hydroxypropyl)-4-methylphenol (3c) (1.6 g, 8.4 mmol) and triphenylphosphine (2.7 g, 10 mmol) in THF (60 mL) was added DIAD at ambient temperature. It was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc (10:1) to give the title compound (3d).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1>>[Cl:22][C:23]1[N:24]=[CH:25][N:26]=[C:27]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)[CH:28]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Clc1cc(Cl)ncn1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(c3cc(Cl)ncn3)CC1)O2

Procedure:
Compound 230 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 4,6-dichloropyrimidine and conditions outlined in procedure AA. M.p.=172-174° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.25 (s, 1H), 7.91-7.86 (m, 2H), 7.76-7.70 (m, 1H), 7.58-7.53 (m, 1H), 7.08 (s, 1H), 3.42-3.33 (m, 4H), 3.10 (s, 2H), 2.09-2.04 (m, 2H), 1.85-1.76 (m, 2H); LCMS: 414 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:23]([C:24]3[C:25](=O)[NH:26][C:27](=[O:31])[N:28]([CH3:30])[CH:29]=3)[C:10]3[N:11]=[C:12]([NH:14][CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:33]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:23]([C:24]3[C:25](=[S:43])[NH:26][C:27](=[O:31])[N:28]([CH3:30])[CH:29]=3)[C:10]3[N:11]=[C:12]([NH:14][CH2:15][CH2:16][N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:33]=1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(NCCN4CCOCC4)nc32)c(=O)[nH]c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(NCCN4CCOCC4)nc32)c(=S)[nH]c1=O

Procedure:
The title product was prepared from the product of step (i) (0.162 g) and Lawesson's reagent (0.7 g) according to the method of example 34 step (iv). Purification was by chromatography eluting with dichloromethane/ethanol/triethylamine mixtures to give the title product as a yellow solid.
Reaction SMILES: [OH-].[K+].[CH:3]1([O:8][C:9]2[C:10]([CH3:19])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([O:16]C)=[S:15])[CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO>[CH:3]1([O:8][C:9]2[C:10]([CH3:19])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([OH:16])=[S:15])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=S)c1cnc(C)c(OC2CCCC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ncc(C(O)=S)cc1OC1CCCC1
Reaction time: 6 h
Yield: 73.7 %

Procedure:
A solution of potassium hydroxide (582 mg) in water (6 mL) is added to a stirred solution of methyl 5-cyclopentyloxy-6-methylthionicotinoate (920 mg) in methanol at room temperature and the mixture stirred for 6 hours. After concentrating in vacuo the mixture is diluted with water and acidified to pH 1 with aqueous 2 M hydrochloric acid. The product is extracted into ethyl acetate, the extracts treated with decolourising charcoal, dried (MgSO4) and evaporated. The residue is triturated with n-pentane to give 5-cyclopentyloxy-6-methylthionicotinic acid (640 mg) as a white solid, m.p. 177-8° C. [Elemental analysis: —C, 56.90; H, 6.02; N, 5.52%. calculated: —C, 56.90; H, 5.97; N, 5.53%.].
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[O:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][CH:13]=1)[CH3:3]>Cl>[CH3:1][N:2]([CH2:4][C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[O:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)[CH3:3]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2CN(C)C)c1
Agent: Cl
Product: CN(C)Cc1ccccc1Oc1cccc(CC(=O)O)c1
Reaction time: 5 h

Procedure:
The ethyl 3-(2-dimethylaminomethylphenoxy)phenyl-acetate acid obtained by the preceding reaction is dissolved in 20 ml of 25% hydrochloric acid and heated under reflux with stirring for five hours. The solvent is then distilled off. The residue is taken up in toluene. The solvent is distilled off again to a residue. The residue is triturated with acetone, the product being obtained in crystalline form. The crystals are filtered off with suction, washed with acetone and air-dried. 3-(2-Dimethylaminomethylphenoxy)-phenylacetic acid, m.p. 205-208°, is obtained.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:9][C:10]1[N:11]=[CH:12][C:13]([NH:16][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:14][CH:15]=1
Reactant: CCCCCC(=O)Cl
Reactant: Nc1ccc(N)nc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCC(=O)Nc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
Hexanoyl chloride (1.1 equiv., 10.08 mmol, 1.36 g) was added dropwise to a cooled (0° C.) suspension of 2,5-diaminopyridine (I13) (1.0 equiv., 9.16 mmol, 1.00 g) and triethylamine (1.1 equiv., 10.08 mmol, 1.02 g) in chloroform (100 ml). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure, and the residue was brought on a filter and successively washed with saturated NaHCO3 solution, water and isopropyl ether. The crude product was further purified by column chromatography (dichloromethane/methanol 95:5; Rf=0.3) to give N-[6-amino-pyridin-3-yl]-hexanamide (I14) (1.24 g, yield=65%). 1H NMR (6, DMSO-D6): 0.87 (3H, t, J=6.9), 1.23-1.33 (4H, m), 1.53-1.60 (2H, m), 2.22 (2H, t, J=7.5 Hz), 5.67 (2H, s), 6.39 (1H, d, J=8.8 Hz), 7.54 (1H, dd, J=8.8, 2.6 Hz), 8.05 (1H, d, J=2.5 Hz), 9.53 (1H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[CH:38](O)=[O:39]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][CH:38]=[O:39])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: NS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Reactant: O=CO
Product: O=CNS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 34.8 %

Procedure:
Using 7-(2,5-dichlorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.10 g, 0.18 mmol) obtained in Example 22 step 5 and formic acid (0.033 mL, 0.89 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.037 g, 34%) was obtained.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH:14]2[CH2:16][CH2:15]2)=O)=[CH:8][CH:7]=1>N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:12]([C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][CH:10]=1)[CH:14]1[CH2:16][CH2:15]1
Reactant: CON
Reactant: O=C(c1ccc(Cl)cc1)C1CC1
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.4 %

Procedure:
Methoxylamine hydrochloride (2.004 g) was added to (4-chlorophenyl)(cyclopropyl)methanone (2.71 g) in pyridine (60 mL) at 25° C. The resulting solution was stirred at 25° C. for 24 hours. The pyridine was removed in vacuo, and the residual solid extracted with ether. Filtration and evaporation of the solvent gave the crude (4-chlorophenyl)(cyclopropyl)methanone O-methyl oxime (2.75 g, 87%) as a yellow oil. This material was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1>>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[N:14][CH:15]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CSc1ccc(B(O)O)cc1
Product: CSc1ccc(-c2ccc(Br)cn2)cc1

Procedure:
Prepared according to the procedure Coupling-2 using [4-(methylthio)phenyl]boronic acid and 2,5-dibromo pyridine afforded the title compound in a mixture of isomer containing 2-bromo-5-[4-(methylthio)phenyl]pyridine.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[C:20]1([N:26]=[C:27]=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][N:6]2[CH2:5][CH2:4][CH:3]([N:2]([CH3:1])[C:27]([NH:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[S:28])[CH2:8][CH2:7]2)=[CH:12]1
Reactant: S=C=Nc1ccccc1
Reactant: CNC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: c1ccccc1
Product: CN(C(=S)Nc1ccccc1)C1CCN(CCc2c[nH]c3ccccc23)CC1
Reaction time: 24 h

Procedure:
3-[2-(4-Methylaminopiperidyl)ethyl]indole (1.28 g, 0.005 mole) was stirred in dry benzene (75 ml) and treated with phenyl isothiocyanate (0.74 g, 0.0055 mole). Stirring was continued for 24 hr. and the mixture evaporated to give the title compound, which was converted to the hydrochloride by addition of hydrogen chloride in ethanol and precipitation with ether. Yield, 0.95 g, m.p. 193.7°.