Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].C[O-].[CH2:27]([N+:34]([CH3:37])([CH3:36])[CH3:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O.CO>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O-:12])=[O:11].[CH2:27]([N+:34]([CH3:37])([CH3:36])[CH3:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: C[O-]
Solvent: CO
Solvent: O
Product: O=C([O-])c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 20 %

Procedure:
A 20% aqueous methanolic solution of the salt is prepared by slurrying 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (22.2 g, 90% pure), in water (50 g) and adding a 40% solution of benzyltrimethylammonium methoxide (27 g) in methanol to pH 8. Additional water (0.8 g) is then added to give the desired concentration.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:20][C:21](=O)[C:22]([F:25])([F:24])[F:23])C>C(O)C>[CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH:13][C:21](=[O:20])[C:22]([F:25])([F:24])[F:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Solvent: CCO
Product: O=C(CC[C@H](NC(=O)C(F)(F)F)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
100 g (421.5 mmol) of L-glutamic acid-5-benzylester is dissolved in a mixture that consists of 1000 ml of trifluoroacetic acid ethyl ester/500 ml of ethanol, and it is stirred for 24 hours at room temperature. It is evaporated to the dry state, and the residue is crystallized from diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:24])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17]C)[C:12]=2[CH:19]2OCC[O:20]2)[CH:5]=[CH:6][CH:7]=1.O.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:24])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[CH:19]=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1nccc(NC[C@@H](O)c2cccc(Cl)c2)c1C1OCCO1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1c(NC[C@@H](O)c2cccc(Cl)c2)cc[nH]c1=O
Temperature: 70 °C
Yield: 10.7 %

Procedure:
To a mixture of (S)-1-(3-chloro-phenyl)-2-(3-[1,3]dioxolan-2-yl-2-methoxy-pyridin-4-ylamino)-ethanol (223 mg, 0.64 mmol) and H2O (0.75 mL) was added HCl solution in dioxane (4 M, 10 mL). After it was heated at 70° C. for 4 h, the reaction mixture was evaporated to dryness. HPLC purification of the residue afforded the title compound (20.1 mg, 11%). 1H NMR (DMSO-d6) δ 3.37 (m, 1H) 3.58 (m, 1H), 4.58 (m, 1H), 5.95 (d, J=6 Hz, 1H), 7.30-7.40 (3H), 7.49 (s, 1H), 9.94 (s, 1H, CHO), 10.30 (m, 1H, NH), 10.95 (m, 1H, 1H). ESI-MS m/z 293.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:13][O:14]/[C:15](/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Br)=[CH:16]/[C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C.C(=O)([O-])[O-].[Ag+2]>[CH3:13][O:14]/[C:15](/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][O:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1)=[CH:16]/[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)/C=C(/OC)c1ccccc1CBr
Reactant: Oc1nc(-c2ccccc2)cs1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)/C=C(/OC)c1ccccc1COc1nc(-c2ccccc2)cs1
Yield: 56.2 %

Procedure:
1.2 g (0.007 mol) of 2-hydroxy-4-phenylthiazole, 2.1 g (0.0077 mol) of silver carbonate and 2.1 g (0.0074 mol) of methyl (E)-β-methoxy-2-bromomethylcinnamate (see Example 2) are stirred in 15 ml of DMF at 60° C. for 8 hours. The precipitate is filtered off and the DMF solution is poured into 100 ml of water, and the mixture is extracted with methyl tert-butyl ether. Drying and concentration of the organic phase result in a brown oil which is chromatographed on silica gel with cyclohexane/acetone (95:5). 1.5 g (56% yield) of methyl (E)-β-methoxy-2-(4-phenyl-2-thiazolyloxymethyl)cinnamate as yellowish oil are isolated as the main fraction.
Reaction SMILES: C(N(CC)[CH2:4][C:5]#[C:6][CH2:7][CH:8]([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)C.S(=O)(=O)(O)[OH:22]>O>[CH3:18][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH2:7][C:6](=[O:22])[CH:5]=[CH2:4]
Reactant: O=S(=O)(O)O
Reactant: CCN(CC)CC#CCC(C)Cc1cccc(OC)c1
Solvent: O
Product: C=CC(=O)CC(C)Cc1cccc(OC)c1

Procedure:
Add mercuric sulphate (0.45 g) to a stirred solution of 1-diethylamino-5-methyl-6-(m-methoxyphenyl)hex-2-yne (8 g) in concentrated sulfuric acid (2.5 cc) and water (25 cc) and heat the mixture at 70° for 11/2 hours. Filter the coled solution, make basic with 10% aqueous sodium hydroxide and extract with ether. Wash and dry the ethereal solution and evaporate to leave as residue crude 1-diethylamino-6-(m-methoxyphenyl)-5-methylhexan-3-one; infrared absorption peaks at 5.85 μ. Slowly distil at 0.1 mm Hg to obtain 5-methyl-6-(m-methoxyphenyl)hex-1-en-3-one; infrared absorption peaks at 5.82 μ.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([Cl:22])[CH:15]=2)[C:8]([O:12][CH3:13])=[C:9]([F:11])[CH:10]=1)=[O:4].CO.[OH-].[Na+].OS([O-])(=O)=O.[Na+]>O>[Cl:22][C:16]1[CH:15]=[C:14]([C:7]2[C:8]([O:12][CH3:13])=[C:9]([F:11])[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COC(=O)c1cc(F)c(OC)c(-c2ccc(OC)c(Cl)c2)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cc(C(=O)O)cc(F)c2OC)cc1Cl
Temperature: 60 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
500 mg of 3′-Chloro-5-fluoro-6,4′-dimethoxy-biphenyl-3-carboxylic acid methyl ester were dissolved using 10 ml of methanol and 1.8 ml of a 1M aqueous NaOH-solution added. The reaction mixture was stirred at 60° C. for 5 h and was then allowed to cool to room temperature. The reaction mixture was then poured into 25 ml of water and acidified to pH=4 using aqueous NaHSO4-solution. The mixture was extracted three times using 20 ml of EA each. The organic layer was dried using MgSO4 and evaporated to yield 430 mg of the title compound that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[NH:8]2)=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.[CH:28](I)([CH3:30])[CH3:29]>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:19])[CH3:20])[CH2:14][CH2:13]3)[N:8]2[CH:28]([CH3:30])[CH3:29])=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1
Reactant: CC(C)I
Reactant: CC(C)(O)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3[nH]2)CC1
Product: CC(C)n1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21

Procedure:
2-(1-((2-Chloro-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.1 g) was reacted with isopropyl iodide via General Procedure C to give 2-(1-((2-chloro-9-isopropyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol which was subsequently reacted with 2-methylbenzimidazole via General Procedure I for Buchwald coupling to give 43.3 g 247 following reverse phase purification. MS (Q1) 533.3 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH2:13][CH2:12][N:11]([S:14]([C:17]2[N:18]=[N:19][NH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:5].[C:31](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:22][CH:23]2[CH2:24][CH2:25]2)[CH2:13][CH2:12][N:11]([S:14]([C:17]2[N:18]=[N:19][N:20]([CH3:31])[CH:21]=2)(=[O:15])=[O:16])[CH2:10][CH2:9]1)=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=C(NCC1(CC2CC2)CCN(S(=O)(=O)c2c[nH]nn2)CC1)c1ccc(Cl)cc1Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(S(=O)(=O)N2CCC(CNC(=O)c3ccc(Cl)cc3Cl)(CC3CC3)CC2)nn1
Temperature: 25 °C

Procedure:
2,4-Dichloro-N-[4-(cyclopropylmethyl)-1-(1H-[1,2,3]triazole-4-sulfonyl)piperidin-4-ylmethyl]benzamide (472 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (5 mL). Potassium carbonate (276 mg, 2 mmol) and methyl iodide (81 μL, 1.3 mmol) were added and the mixture stirred at room temperature over night.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]#[CH:51]>CC([O-])=O.CC([O-])=O.[Pd+2].CC#N>[Cl:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]#[C:51][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1Cl
Reactant: C#CCCCCCl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Nc1cccnc1C#CCCCCCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.4 %

Procedure:
A mixture of 2-chloropyridin-3-amine (2571 mg), K2CO3 (8292 mg), Pd(OAc)2 (180 mg), dppb (682 mg) and CH3CN (25 mL) was stirred at room temperature under Ar atmosphere for 30 min. 6-Chlorohex-1-yne (2565 mg) was added to the mixture, and the mixture was stirred at 80° C. under Ar atmosphere for 24 h. The mixture was filtrated and insoluble material was washed with CH3CN. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (600 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:9](=[CH2:10])[CH:8]2[CH2:11][CH2:12][CH:13]([C:14]([OH:16])=[O:15])[C:6]32[CH2:7][CH:3]1[CH2:4][CH2:5]3.C(O)=O.C(O)C>O>[CH3:10][C:9]1[C:2]([CH3:1])([CH3:17])[CH:3]2[CH2:7][C:6]3([CH2:5][CH2:4]2)[C:8]=1[CH2:11][CH2:12][CH:13]3[C:14]([OH:16])=[O:15]
Reactant: C=C1C2CCC(C(=O)O)C23CCC(C3)C1(C)C
Solvent: O
Solvent: O=CO
Solvent: CCO
Product: CC1=C2CCC(C(=O)O)C23CCC(C3)C1(C)C

Procedure:
500 mg of vetivenic acid (see example 1) were treated with formic acid under the same conditions as those described in example 2. The pure compound was obtained after cristallization in a 1:1 mixture of ethanol and water.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19].[NH3:27]>C(COC)OC.C(OCC)(=O)C>[NH2:27][C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19]
Reactant: N
Reactant: Cn1c(-c2cccc(F)c2)nc2c(Cl)nc(C#CC3(O)CCCC3)nc21
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(O)CCCC3)nc21
Temperature: 70 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
1-{2-[6-Chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl)-1-ethynyl}-1-cyclopentanol (732 g) was dissolved in 16 liters of dimethoxyethane, 8 liters of a concentrated aqueous ammonia were added and the mixture was stirred at 70° C. for 5 hours using a sealed tube reactor. After the reaction solution was cooled in room temperature, it was diluted with 20 liters of ethyl acetate and washed with water twice (8 liters and 4 liters). The organic layer was concentrated to about 15 liters and the resulting residue was diluted with 15 liters of hexane, filtered and washed with hexane twice. Then it was dried at 50° C. for 2.5 hours to give 620 g of the product. The yield was 89%.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:16]([C:17]([OH:19])=O)=[C:15]([F:25])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)C([O:30][CH2:31][CH2:32][CH2:33][NH:34][S:35](=[O:38])(=[O:37])[NH2:36])=O.C(=O)([O-])[O-].[Na+].[Na+].Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4[CH2:23][CH2:24]4)=[CH:20][C:16]([C:17]([NH:36][S:35](=[O:38])(=[O:37])[NH:34][CH2:33][CH2:32][CH2:31][OH:30])=[O:19])=[C:15]([F:25])[CH:14]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: NS(=O)(=O)NCCCOC(=O)C(F)(F)F
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NS(=O)(=O)NCCCO)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.3 %

Procedure:
To a stirred solution of 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid (0.30 g, 0.87 mmol) in dichloromethane (15 mL) were added N-(3-dimethyl-aminopropyl)-N′-ethylcarbodiimide hydrochloride (0.38 g, 2.00 mmol) and 4-(dimethylamino)pyridine (0.25 g, 2.00 mmol). The reaction stirred at ambient temperature for 10 min, 3-(sulfamoylamino)propyl 2,2,2-trifluoroacetate (0.50 g, 2.00 mmol) was added and stirring continued at ambient temperature for 72 h. sodium carbonate solution (3M, 10 mL) was added and stirred at ambient temperature for 4 h, aqueous hydrochloric acid (3N) were added to pH=1 and diluted with ethyl acetate (200 mL), washed with water and brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by reversed-phase column chromatography afforded the title compound as colorless solid (0.11 g, 27%): 1H NMR (300 MHz, DMSO-d6) 11.50 (s, 1H), 7.66 (br s, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.90 (d, J=12.9 Hz, 1H), 4.45 (t, J=5.0 Hz, 1H), 3.63 (s, 2H), 3.43-3.37 (m, 2H), 3.00-2.93 (m, 2H), 2.07-1.99 (m, 4H), 1.75-1.56 (m, 14H), 0.93-0.87 (m, 2H), 0.69-0.64 (m, 2H); MS (ES+) m/z 481.2 (M+1); MS (ES−) m/z 479.3 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][CH2:20][C:19]=3[CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH:26]O>>[CH3:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][CH2:20][C:19]=3[CH:25]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2ccc3c(c2)COC(=O)N3)cc1C
Product: Cc1ccc(S(=O)CCCCOc2ccc3c(c2)COC(=O)N3)cc1C

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dimethyl-phenylmercapto)-butoxy]-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][NH:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2Sc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)NCc1ccccc1S2

Procedure:
To a stirring solution of 5.23 g (20 mmol) of 8-chlorodibenzo[b,f][1,4]thiazepin-11(10H)-one (34), prepared in the manner described above in Example 34, in 175 mL of THF cooled in an ice bath is added dropwise 100 mL of M lithium aluminum hydride solution. The reaction is heated at reflux for 4 hours. The reaction is quenched by the addition of 3.8 mL of 15% NaOH and 15.2 mL of H2O. The reaction mixture is filtered through a pad of celite. The filtrate is concentrated in vacuo and is recrystallized from cyclohexane.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH2:11][CH3:12])=[N:7][CH:8]=[CH:9][CH:10]=1)(=O)C.[Li+].[OH-]>C(O)C>[CH2:11]([C:6]1[C:5]([OH:4])=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:12]
Reactant: CCc1ncccc1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ncccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
To a solution of 2-ethylpyridin-3-yl acetate (5.1 g, 31 mmol) in ethanol (50 mL) was added 3M LiOH (50 mL, 150 mmol). The reaction mixture stirred at ambient temperature for 30 minutes. The mixture was concentrated to dryness and purified over silica gel (10% MeOH in CH2Cl2) to afford 2-ethylpyridin-3-ol (2.5 g, 20 mmol).
Reaction SMILES: C[CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]3[C:22]([N:23]=[C:24]4[CH2:30][CH2:29]CC[CH2:26][C:25]=24)=[CH:21][CH:20]=[N:19]3)=[CH:13][CH:12]=1.ClCCC[O:35]C1C=CC(C2N3C(=CC=N3)N=C3C=2CCC3)=CC=1.O[C@H]1CCNC1>>[N:19]1[N:18]2[C:22]([N:23]=[C:24]3[C:25](=[C:17]2[C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:3]4[CH2:4][CH2:5][C@H:6]([OH:35])[CH2:2]4)=[CH:12][CH:13]=2)[CH2:26][CH2:29][CH2:30]3)=[CH:21][CH:20]=1
Reactant: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1
Reactant: CC1CCCN1CCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Agent: O[C@H]1CCNC1
Product: O[C@H]1CCN(CCCOc2ccc(-c3c4c(nc5ccnn35)CCC4)cc2)C1

Procedure:
Using the method described for the preparation of 10-{4-[3-(2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 8-[4-(3-chloro-propoxy)-phenyl]-6,7-dihydro-5H-1,4,8a-triaza-s-indacene and 3-(S)-hydroxy-pyrrolidine provided the title compound.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:19][CH2:20]OC)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])C.[CH:23]1([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1.[Cl-].C[Al+]C.Cl>C1(C)C=CC=CC=1>[CH:23]1([C:26]2[CH:32]=[CH:31][C:29]([N:30]3[CH2:20][CH2:19][C:6]4([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]4)[C:4]3=[O:5])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Nc1ccc(C2CC2)cc1
Agent: C[Al+]C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(c2ccc(C3CC3)cc2)CCC12CCNCC2
Temperature: 115 °C
Reaction time: 15 h

Procedure:
A mixture of 1.3 g (4.1 mmol) 4-(2-Methoxy-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester, 0.604 g (4.5 mmol) 4-cyclopropylaniline and 8.24 mL (8.24 mmol) dimethylaluminum chloride (1N in hexane) in 100 mL toluene was stirred at 115° C. for 15 h. After cooling to room temperature the mixture was poured into ice, the mixture was acidified with HCl aq. to pH=2 and extracted with ethyl acetate. The aqueous layer was basified with NaOH pellets to pH=8 and extracted with DCM. The combined organic layers were dried with MgSO4 and evaporated to dryness. The residue was purified by column chromatography on silica (amine) with a gradient formed from ethyl acetate and methanol to yield after evaporation of the product containing fractions 0.468 g (42%) of the title compound as light yellow solid. MS m/e: 270.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:16])=O>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([Cl:16])=[O:13])=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C(=O)O)nc1
Reactant: O=S(Cl)Cl
Product: CCCCc1ccc(C(=O)Cl)nc1

Procedure:
A solution of 5-butylpicolinic acid (1 mL) in thionyl chloride (24 eq.) was heated at 60-70° C. for 1 hour to form 5-butylpicolinoyl chloride. Excess of thionyl chloride was removed. Methyl 2-(5-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 2, 200 mg) in DCM (5 mL) and pyridine (5 mL) was added to 5-butylpicolinoyl chloride and the reaction mixture was stirred for 1 hour at RT. Solvent was removed and ether was added to it. The solution was stirred, filtered, washed with water and dried obtain the title compound. 1H NMR (DMSO-d6; 300 MHz): δ 10.81 (s, 1H), 8.57 (d, 1H), 8.60 (s, 1H), 8.41 (s, 1H), 8.12 (m, 3H), 7.92 (d, 1H), 7.81 (d, 2H), 4.35 (t, 1H), 3.68 (s, 3H), 2.75 (t, 2H), 2.28 (m, 1H), 1.64 (m, 2H), 1.37 (m, 2H), 0.97 (m, 9H); MS (ESI) m/z 495.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[CH:14]([Sn](C=C)(C=C)C=C)=[CH2:15].[Cl-].[Li+]>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.CN(C=O)C>[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([CH:14]=[CH2:15])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)([CH3:13])[CH3:12]
Reactant: C=C[Sn](C=C)(C=C)C=C
Reactant: CC(C)c1nnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1ccc2nnc(C(C)C)n2n1
Temperature: 85 °C
Yield: 39.9 %

Procedure:
The 6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (8.60 g, 43.7 mmol, Preparation #G.1), tetravinylstannane (11.91 g, 52.50 mmol), PdCl2(PPh3)2 (3.07 g, 4.37 mmol) and lithium chloride (3.71 g, 87.0 mmol) were added to DMF (65 mL) and then the mixture was heated to about 85° C. for about 1 h. The reaction was cooled to ambient temperature and then concentrated under reduced pressure. Water and EtOAc were added to the residue and then the mixture was filtered through Celite®. The filtrate was transferred to a separatory funnel and the layers were separated then the aqueous layer was extracted with EtOAc. The combined organic solutions were dried over MgSO4 and filtered prior to concentrating under reduced pressure to provide an oil which was purified by flash chromatography on silica gel with EtOAc as an eluent. The material was purified further by flash chromatography on silica gel with DCM/MeOH (95:5) as an eluent to give the title compound (3.28 g, 39.8%) as a light yellow oil which crystallized on standing: 1H NMR (DMSO-d6) δ 1.39 (d, 6H), 3.53 (m, 1H), 5.84 (d, 1H), 6.44 (d, 1H), 6.82 (dd, 1H), 7.69 (d, 1H), 8.28 (d, 1H); LC/MS (Table 1, Method a) Rt=2.06 min; MS m/z: 189.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:19][CH:9]2[CH2:10][NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:7]([C:8]=32)[CH2:6]1)[CH2:2][CH3:3]>C(O)(=O)C.[Pd].CO.[O-2].[O-2].[Mn+4]>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:19][C:9]2=[CH:10][NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:7]([C:8]=32)[CH2:6]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2c(C(N)=O)ccc3c2C(CN3)C1
Agent: [Mn+4]
Agent: [Pd]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)C1Cc2c[nH]c3ccc(C(N)=O)c(c23)C1

Procedure:
The following enantiomer of the compound of Formula I ##STR9## can be prepared from the compound of Formula VII by reaction with an approximately equimolar mixture of carbon monoxide and ammonia in the presence of a catalyst, preferably a palladium catalyst such as bis(triphenylphosphine)palladium chloride or bis(triphenylphosphine)palladium bromide. The catalyst is preferably present in a ratio of about 0.05 mole per mole of reaction substrate. The preferred solvent is toluene, and the concentration of the reactant is about 0.5 to about 2.0 grams per 100 milliliters of solvent. The reaction vessel is sealed and the reaction mixture stirred at approximately 100° C. for approximately 6 hours. The use of such catalysts for the reaction of arylhalides with carbon monoxide is disclosed by Schoenberg and Heck, Journal of Organic Chemistry, 39, p. 3325 (1974) and Schoenberg, Bartoletti and Heck, Journal of Organic Chemistry, 39, p. 3318, (1974). The benzoyl group can then be removed by any of a number of methods known to the art, but preferably by reaction with approximately 4 equivalents of n-butyl lithium in freshly distilled tetrahydrofuran. The deprotection reaction is conducted at about -78°. The reaction is quenched by the addition of 1:1 (volume:volume) water and tetrahydrofuran, and the resulting 4-(di-n-propyl)amino-6-aminocarbonyl-1,2,2a,3,4,5-hexahydrobenz[cd]indole is isolated by evaporation of the tetrahydrofuran, extraction from the aqueous phase into a solvent such as methylene chloride, and evaporation of the solvent. Oxidation of the hexahydrobenz-[cd]indole by reaction with manganese dioxide in acetic acid by the method disclosed by Flaugh in U.S. Pat. No. 4,576,959 or palladium on carbon in methanol affords the desired 4-(di-n-propyl)amino-6-aminocarbonyl-1,3,4,5-tetrahydrobenz[cd]indole.