Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[C:6]([O:10][C:11]([C@H:13]1[CH2:15][C@H:14]1[CH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[O:21])=[O:12])([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([N:18]1[CH2:19][CH2:20][CH:16]([CH:14]2[CH2:15][CH:13]2[C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])[C:17]1=[O:21])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H]1C1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C1CC1C1CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.8 %

Procedure:
To 30 ml of a dimethylformamide solution of 2.288 g (10.2 mmol) of 3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one was added 406.2 mg (10.2 mmol) of sodium hydride under cooling with ice, followed by stirring at room temperature for 1.5 hours. Then, 1.81 ml (15.3 mmol) of benzyl chloride was added thereto dropwise, followed by stirring for 2.5 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 1.121 g (35.0%) of 1-benzyl-3-(2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one (isomer A: an isomer attributed to the steric configuration of the cyclopropyl group bonded to the carbon atom of the pyrrolidine ring) as a colorless solid. The column was then eluted with hexane:ethyl acetate=l:l to give 670.9 mg (20.9%) of 1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one (isomer B: an isomer attributed to the steric configuration of the cyclopropyl group bonded to the carbon atom of the pyrrolidine ring) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([N:28]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(NS(C2C3C(=CC=CC=3)C(N3C(=O)C4C(=CC=CC=4)C3=O)=CC=2)(=O)=O)=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([NH2:28])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(N3C(=O)c4ccccc4C3=O)c3ccccc23)CC1
Agent: COc1ccc(NS(=O)(=O)c2ccc(N3C(=O)c4ccccc4C3=O)c3ccccc23)cc1
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(N)c3ccccc23)CC1

Procedure:
4-(4-Amino-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (20) was prepared according to the general procedure in Scheme 3 substituting 4-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-naphthalene-1-sulfonyl amino] -piperidine-1-carboxylic acid tert-butyl ester for 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-naphthalene-1-sulfonic acid (4-methoxyphenyl)-amide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:12]([CH:14](N(C)C)[CH3:15])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:26]1[C:27]2[CH:34]([CH2:35][CH3:36])[C:33](=[O:37])[NH:32][C:28]=2[N:29]=[CH:30][N:31]=1.C[CH2:39][N:40](C(C)C)[CH:41](C)C>CC(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([CH:19]3[CH2:20][CH2:21][N:22]([C:26]4[C:27]5[CH:34]([CH2:35][CH3:36])[C:33](=[O:37])[NH:32][C:28]=5[N:29]=[CH:30][N:31]=4)[CH2:23][CH2:24]3)[N:12]([CH2:14][CH2:15][N:40]([CH3:41])[CH3:39])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(N(C)C)n1cc(-c2ccc(F)c(F)c2)nc1C1CCNCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCC1C(=O)Nc2ncnc(Cl)c21
Solvent: CC(C)O
Product: CCC1C(=O)Nc2ncnc(N3CCC(c4nc(-c5ccc(F)c(F)c5)cn4CCN(C)C)CC3)c21
Yield: 26.2 %

Procedure:
Combine 2-(4-(3,4-difluorophenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl-N,N-dimethyl ethanamine (0.35 g; 0.0010 mol; 1.0 equiv), 4-chloro-5-ethyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.23 g; 0.0011 mol; 1.1 equiv), DIPEA (0.72 mL; 0.0041 mol; 4.0 equiv) in IPA (10 mL) and stir at 90° C. for 16 h. Quench the reaction with demineralized water and extract with EA. Evaporate the organic layer, purify over a silica gel column with 0-10% MeOH/DCM to give the title compound (0.13 g; 24.13%). MS (ES+): m/z=496 (M+H).
Reaction SMILES: [CH2:1]=[O:2].[O:3]=[C:4]1[CH:11]2[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:13][CH:5]1[CH:6]3O)[CH2:10]2.[ClH:15]>>[Cl:15][CH2:1][O:2][CH:10]1[CH:11]2[CH2:12][CH:7]3[CH2:6][CH:5]([CH2:13][CH:9]1[CH2:8]3)[C:4]2=[O:3]
Reactant: C=O
Reactant: Cl
Reactant: O=C1C2CC3CC(C2)C(O)C1C3
Product: O=C1C2CC3CC(C2)C(OCCl)C1C3
Reaction time: 12 h

Procedure:
Paraformaldehyde was added to 4-oxo-2-hydroxyadamantane, and a hydrogen chloride gas was injected at 2.5 equivalent amounts per this 4-oxo-2-hydroxyadamantane. Then, the reaction was conducted at a temperature of 50° C. for 12 hours. After the completion of the reaction, the product was distillated under reduced pressure so as to obtain 4-oxo-2-adamantyl chloromethyl ether (compound 1) represented by the following chemical formula (58).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Si:7]([O:14][C@H:15]1[C@H:19]2[O:20][CH2:21][C:22](=O)[C@H:18]2[O:17][CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.O>[C:10]([Si:7]([CH3:8])([CH3:9])[O:14][C@@H:15]1[CH2:16][O:17][C@@H:18]2[C:22](=[CH2:1])[CH2:21][O:20][C@H:19]12)([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@@H]2C(=O)CO[C@@H]21
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CO[C@H]2[C@@H]1OC[C@H]2O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 234.7 %

Procedure:
A stirred suspension of methyltriphenylphosphonium bromide (1.84 g, 5.16 mmol) and potassium tert-butoxide (578 mg, 5.16 mmol) in tetrahydrofuran (15 mL) was heated at reflux under an atmosphere of argon for 3 hours then allowed to cool to ambient temperature. A solution of ketone (87) (888 mg, 3.44 mmol) in tetrahydrofuran (7.5 mL) was added then heating at reflux continued for 2.25 hours. The mixture was diluted with water (30 mL) then the product extracted into diethyl ether (2×30 mL). The combined organic layers were washed with brine (25 mL), dried (MgSO4), filtered and reduced in vacuo to leave residue (2.07 g). Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 0:100 to 15:85 gave alkene (88) as a colourless oil (799 mg, 91%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C.O>ClCCl>[CH2:2]([NH:1][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCN
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 1-aminododecane (5.67 g, 30 mmol), methanesulfonyl chloride (2.52 ml, 32.6 mmol) and triethylamine (4.5 ml, 32.6 mmol) in dichloromethane (30 ml) was stirred at room temperature for 14 hours. The mixture was poured into water and the layers were separated. Evaporation of the dried (magnesium sulfate) organic layer gave a solid, which after trituration with cold hexane gave the title sulfonamide. 1HNMR(CDCl3): 0.92 (t, 3H, J=7.1 Hz), 1.29 (br s, 18H), 1.60 (2H), 2.99 (s, 3H), 3.16 (dd, 2H, J=13.3 Hz, 6.4 Hz) and 4.25 (br, 1H). HRMS exact mass calculated for C13H30NO2 (M+H)+ 264.1997, found 264.1993.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[C:17]([C:19]1[CH:30]=[C:29]([CH3:31])[C:22]2[NH:23]C(=O)[O:25][C:26](=O)[C:21]=2[CH:20]=1)#[N:18].N1C=CC=C(C)C=1.CS(Cl)(=O)=O>C(#N)C.O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:9][C:26](=[O:25])[C:21]3[CH:20]=[C:19]([C:17]#[N:18])[CH:30]=[C:29]([CH3:31])[C:22]=3[N:23]=2)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: Cc1cc(C#N)cc2c(=O)oc(=O)[nH]c12
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: Cc1cccnc1
Solvent: CC#N
Product: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
A mixture of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (97.9% purity, 3.09 g, 10.0 mmol), 6-cyano-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (96.3% purity, 2.10 g, 10.0 mmol) and 3-picoline (3.30 mL, 3.16 g, 34 mmol) in acetonitrlle (65 mL) was cooled to about −5° C. Then methanesulfonyl chloride (1.0 mL, 1.5 g, 13 mmol) in acetonitrile (3 mL) was added dropwise at −5 to 0° C. After 15 minutes at −5 to 0° C., the reaction mixture was heated to 50° C. for 4 hours. The reaction mixture was then cooled to room temperature, water (4 mL) was added dropwise, and the reaction mixture was stirred 15 minutes. The mixture was filtered, and the solids were washed sequentially with 4:1 acetonitrile-water (2×2 mL) and acetonitrile (3×2 mL), and dried under nitrogen to afford the title product as a pale green powder, 3.71 g (94.2% purity by HPLC, 82.0% yield calculated based on the purity), melting at 263-267° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].N12CCCNC1CCCC=C2.O>CN(C)C=O>[N:17]1[CH:16]=[CH:15][N:14]2[C:9]([S:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:20]3[C:21](=[O:23])[CH2:22][S:18][C:19]3=[O:24])(=[O:8])=[O:7])=[CH:10][CH:11]=[CH:12][C:13]=12
Reactant: O=S(=O)(CCCCCl)c1cccc2nccn12
Reactant: O=C1CSC(=O)N1
Agent: C1=CN2CCCNC2CCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CSC(=O)N1CCCCS(=O)(=O)c1cccc2nccn12
Temperature: 80 °C

Procedure:
To a solution of 0.27 g (1.0 mmol) of 5-(4-chlorobutylsulfonyl)imidazo[1,2-a]pyridine and 0.177 g (1.0 mmol) of thiazolidine-2,4-dione in 7 ml of N,N-dimethylformamide, 0.15 ml (1.0 mmol) of 1,8-diazabicyclo[5.4.0]-undecene was added, followed by heating at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform→chloroform/methanol=50/1) to yield 0.22 g (62.2%, light yellow oily substance) of the desired product.
Reaction SMILES: [Zr:1].[CH2:2]([OH:5])[CH2:3][CH3:4].[CH2:6]1[O:9][CH:7]1[CH3:8]>C(N(CC)CC)C>[O-:5][CH2:2][CH2:3][CH3:4].[Zr+4:1].[O-:9][CH2:6][CH2:7][CH3:8].[O-:5][CH2:2][CH2:3][CH3:4].[O-:5][CH2:2][CH2:3][CH3:4]
Reactant: [Zr]
Reactant: CC1CO1
Reactant: CCCO
Solvent: CCN(CC)CC
Product: CCC[O-]
Product: [Zr+4]

Procedure:
European Patent No. 369,979 (1989) discloses a way of making fine spherical powders of amorphous hydrated zirconium oxide. In the given example, a process was described in which zirconium oxychloride octahydrate (ZrOCl2.8H2O) was dissolved in 2-methoxyethanol at 60° C. and it was claimed that water was removed as an azeotropic mixture of water and 2-methoxyethanol to produce an essentially anhydrous zirconium salt. It was further claimed that to this zirconium salt was added n-propanol followed by the successive additions of propylene oxide and triethylamine to afford an organic solution of zirconium propoxide. This intermediate zirconium compound was then treated with a mixture of water, oleic acid and n-propanol to effect the hydrolysis and to produce spherical particles of zirconium oxide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12](I)[CH:11]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[C@:27]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:36])[CH2:26]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]2[C@:27]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]([C:12]4[CH:13]=[CH:14][CH:15]=[C:10]([C:9]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[O:17])[CH:11]=4)[C:28]3=[O:36])[CH2:26]2)=[CH:23][CH:24]=1
Reactant: C1COCCN1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(I)c1
Product: O=C(c1cccc(N2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1)N1CCOCC1

Procedure:
The title compound was prepared in analogy to Example 85 starting from morpholine, methyl-3-iodobenzoate (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C27H23ClN2O3: 458, observed (M+H)+: 459.1 1H NMR (400 MHz, MeOD-d4) δppm 2.34 (dd, J=8.97, 4.93 Hz, 1 H) 2.44 (dd, J=8.59, 5.05 Hz, 1 H) 3.35-3.39 (m, 1 H) 3.67 (br. s., 8 H) 6.96 (d, J=7.83 Hz, 1 H) 7.17-7.26 (m, 2 H) 7.26-7.36 (m, 5 H) 7.41 (s, 1 H) 7.46-7.52 (m, 2 H) 7.64 (t, J=7.83 Hz, 1 H).
Reaction SMILES: S(OCCCC1C2C=C(F)C=CC=2OC=1)(C1C=CC(C)=CC=1)(=O)=O.[S:25]([O:35][CH2:36][CH2:37][C:38]#[C:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=1Br)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26].[SnH](CCCC)(CCCC)CCCC>>[S:25]([O:35][CH2:36][CH2:37][CH2:38][C:39]1[C:43]2[CH:44]=[C:45]([Cl:48])[CH:46]=[CH:47][C:42]=2[O:41][CH:40]=1)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)OCCC#CCOc2ccc(Cl)cc2Br)cc1
Agent: CCCC[SnH](CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)OCCCc2coc3ccc(F)cc23)cc1
Product: Cc1ccc(S(=O)(=O)OCCCc2coc3ccc(Cl)cc23)cc1

Procedure:
The title compound was prepared (2.17 g, 57%) in a manner analogous to the preparation of 5-fluoro-3-benzo[b]furanpropanol tosylate (Example 21) by the reaction of 5-(2-bromo-4-chlorophenoxy)pent-3-yn-1-ol tosylate with n-Bu3SnH.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Cl[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28].C(N(CC)CC)C>C(O)C>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])=[C:20]([N+:27]([O-:29])=[O:28])[CH:21]=1)#[N:24]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCCC1Cc1c[nH]c2ccc(Nc3ccc(C#N)cc3[N+](=O)[O-])cc12
Yield: 80 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole end 4-chloro-3-nitrobenzonitrile were used. Triethylamine was used as base, absolute ethanol was used as solvent, and the reaction was heated at reflux for 4 hours. Column chromatography afforded the title compound (80%) as a red solid: mp, 170°-171.0° C.; 13C NMR (CDCl3) δ147.3, 137.1, 135.4, 132.0, 131.4, 128.6, 128.0, 125.3, 120.6, 117.9, 117.1, 116.3, 113.1, 111.9, 99.1, 68.1, 57.3, 40.6, 31.2, 28.1, 21.9, Anal. calcd for C21H21N5O2.0.05 CH2Cl2 : C, 66.59; H, 5.60; N, 18.44. Found: C, 66.56; H, 5.26; N, 18.42.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].ClC1C=CC(OC)=C(I)C=1[F:21].[F:22][C:23]([F:32])(S(F)(=O)=O)C(OC)=O>[Cu](I)I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:23]([F:32])([F:21])[F:22])[C:3]=1[F:10]
Reactant: COC(=O)C(F)(F)S(=O)(=O)F
Reactant: COc1ccc(Cl)c(F)c1I
Reactant: COc1ccc(Cl)c(F)c1
Agent: I[Cu]I
Product: COc1ccc(Cl)c(F)c1C(F)(F)F

Procedure:
1-Chloro-2-fluoro-4-methoxybenzene was converted to 1-chloro-2-fluoro-3-iodo-4-methoxybenzene (see G. L. Grunewald et al., J. Med. Chem. 1986, 29, 1972-1982). 1-Chloro-2-fluoro-3-iodo-4-methoxybenzene was treated with methyl difluoro(fluorosulfonyl)acetate in the presence of copper iodide (A. Khilevich et al., U.S. Pat. Appl. Publ. 2010, US 20100016373) to provide 1-chloro-2-fluoro-4-methoxy-3-(trifluoromethyl)benzene. 4-Chloro-3-fluoro-2-(trifluoromethyl)phenol was then obtained by de-methylation using boron trichloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][C@@H:18](O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1C(COC(/N=N\C(OCC2C=CC(Cl)=CC=2)=O)=O)=CC=C(Cl)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Agent: O=C(/N=N\C(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cncc(Br)c2)C1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-7, 5-bromopyridin-3-ol was reacted with (R)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as a light yellow oil. MS: 357.1 and 359.1 (M+H+).
Reaction SMILES: [CH2:1]([C:5]([CH2:12][CH3:13])([CH2:8][CH2:9][C:10]#[N:11])[CH:6]=O)[CH2:2][CH2:3][CH3:4].[NH3:14].[H][H]>>[CH2:1]([C:5]1([CH2:12][CH3:13])[CH2:8][CH2:9][CH2:10][NH:11][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH2:1]([C:5]([CH2:12][CH3:13])([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][NH2:14])[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCC(C=O)(CC)CCC#N
Reactant: N
Product: CCCCC(CC)(CN)CCCN
Product: CCCCC1(CC)CCCNC1

Procedure:
Example 1 was repeated using 2-butyl-2-ethyl-4-cyanobutanal as the starting material. To this end, 33.6 g per hour of 2-butyl-2-ethyl-4-cyanobutanal (purity 89.0%, 29.9 g, 0.165 mol) and 1344 ml (806 g, 47.4 mol) per hour of liquid ammonia were pumped at 250 bar and 60° C. through the imination reactor. The product stream was subsequently passed through the hydrogenation reactor from bottom to top at 250 bar and 120° C. while simultaneously passing 100 l(S.T.P.)/h (4.5 mol) of hydrogen through the reactor. The product stream was decompressed to atmospheric pressure and NH3 was removed by distillation. The product from 16.7 hours was separated by fractional distillation on a 30 cm packed column (3 mm glass rings), giving 166.8 g of 3-butyl-3-ethylpiperidine (b.p.=73° to 75° C./2 mmHg) and 267.5 g of 2-butyl- 2-ethylpentane-1,5-diamine (b.p.=105° C./2 mmHg). The diamine yield was 52.1% of theory.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=[CH:16][C:17]=3[O:19][CH3:20])[CH:12]=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CO.O>[CH3:20][O:19][C:17]1[CH:16]=[CH:15][C:14]([N+:21]([O-:23])=[O:22])=[C:13]2[C:18]=1[NH:10][CH:11]=[CH:12]2
Reactant: COc1ccc([N+](=O)[O-])c2ccn(S(=O)(=O)c3ccccc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c2cc[nH]c12

Procedure:
To a solution of 1-benzenesulfonyl-7-methoxy-4-nitro-1H-indole (R) (1 eq) in methanol was added a solution of sodium hydroxide (5 eq) in water. The solution was heated to reflux for 3 hrs. Methanol was removed under reduced pressure then water and ethyl acetate were added. The ethyl acetate layer separated and washed repeatedly (3×) with water. The ethyl acetate layer was concentrated and evaporated to dryness to produce the desired product.
Reaction SMILES: C1([Si](C2C=CC=CC=2)(C2C=CC=CC=2)[C:8]#[C:9][C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])C=CC=CC=1.[C:31](=[O:33])=[O:32]>ClCCl.CO.C(O)(=O)C>[Cl:16][C:15]1[CH:14]=[C:13]([Cl:17])[CH:12]=[C:11]([Cl:18])[C:10]=1[C:9]#[C:8][C:31]([OH:33])=[O:32]
Reactant: O=C=O
Reactant: Clc1cc(Cl)c(C#C[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)C#Cc1c(Cl)cc(Cl)cc1Cl

Procedure:
Prepared analogously to Example 4.3.a. from triphenyl-(2,4,6-trichlorophenylethynyl)silane and dry ice. Yield: 3.3 g (77.7% of theory); melting point: 170° C.-175° C.; C9H3Cl3O2 (M=249.48); calc.: molecular ion peak (M+H)+: 249/251/253; found: molecular ion peak (M+H)+: 249/251/253; Rf value: 0.4 (silica gel, dichloromethane/methanol/acetic acid (50:10:1)).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:18])=[CH:12]3)[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.O>[CH3:18][C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:7]=1)=[CH:17][CH:16]=2
Reactant: Cc1cc2cc(Nc3ccnc(Cl)n3)ccc2[nH]1
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2cc(Nc3ccnc(Nc4ccccc4)n3)ccc2[nH]1
Temperature: 60 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
N-(2-chloropyrimidin-4-yl)-2-methyl-1H-indol-5-amine (0.1 mmol) and aniline (0.1 mmol) were dissolved in 0.5 ml DMF. To this was added p-TsOH monohydrate (0.2 mmol). The reaction mixture was stirred at 60° C. for 5 hours, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified by column chromatography to provide the title product in a yield of 85%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][CH:19]([N:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[CH2:18][CH2:17]4)=[N:12][N:11]3[C:27]=2[C:28]2[CH:33]=[CH:32][N:31]=[C:30]3[N:34](S(C4C=CC(C)=CC=4)(=O)=O)[CH:35]=[CH:36][C:29]=23)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][CH:19]([N:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[CH2:18][CH2:17]4)=[N:12][N:11]3[C:27]=2[C:28]2[CH:33]=[CH:32][N:31]=[C:30]3[NH:34][CH:35]=[CH:36][C:29]=23)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(N6CCC(N7CCCC7)CC6)nn45)ccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Fc1ccc(-c2nc3ccc(N4CCC(N5CCCC5)CC4)nn3c2-c2ccnc3[nH]ccc23)cc1

Procedure:
The 2-(4-fluorophenyl)-6-(4-pyrrolidin-1-ylpiperidin-1-yl)-3-[1-(4-methylphenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazine obtained in step 6.1 is dissolved in 3 ml of a mixture of methanol and tetrahydrofuran (2/1), then treated using 0.09 ml (0.54 mmol) of a 6N aqueous solution of sodium hydroxide at 60° C. for 1 and a half hours. The solvent is evaporated and the residue taken up in 3 ml of water. The product is extracted 2 times with 3 ml of dichloromethane. The organic phase is dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The residue obtained is then purified by chromatography over a silica gel column (4 g) by eluting with a gradient of dichloromethane, methanol and aqueous ammonia (of 95/5/05 to 90/10/1) in order to give 0.064 g of 2-(4-fluorophenyl)-6-(4-pyrrolidin-1-ylpiperidin-1-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine after crystallization in 10 ml of acetonitrile, filtration and drying.
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:17])([CH3:16])[CH2:11][C:12]2=[O:15])=[CH:8][CH:7]=1>O.F[B-](F)(F)F.[H+]>[OH:2][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:17])([CH3:16])[CH2:11][C:12]2=[O:15])=[CH:8][CH:7]=1
Reactant: O=N[O-]
Reactant: CC1(C)CC(=O)c2cc(N)ccc21
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CC1(C)CC(=O)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
A solution of sodium nitrite (14.8 g, 214 mmol) in 30 mL of water was slowly added to the solution of 6-amino-3,3-dimethyl-indan-1-one (14.0 g, 85.8 mmol) in 30 mL of 48% tetrafluoroboric acid and 30 mL of water at 0°-5° C. After being stirred for 30 min, the mixture was filtered, and the solids were washed with cold 5% tetrafluoroboric acid and dried in vacuum. The solids were then added in several portions into a boiling solution of 50 mL of sulfuric acid in 0.5 liter of water. After refluxing for 1 hour, the solution was cooled to room temperature and extracted with ethyl acetate (100 mL×3). The combined extracts were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (EtOAc:hexane=1:10 to 1:2) to give 7.60 g (50% yield) of the title compound as a solid; 1H-NMR (CDCl3) δ1.40 (s, 6H), 2.64 (s, 2H), 7.13 (s, 1H),7.18 (d, J=8.2 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H); MS m/e 177 (MH+).