Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C:6]1[C:7]2[S:24][C:23](=[O:25])[NH:22][C:8]=2[N:9]=[C:10]([S:12]([CH2:15][C:16]2C=C[CH:19]=[CH:18][CH:17]=2)(=O)=O)[N:11]=1)[CH3:4].[S:26]1C=CC=C1CS>>[OH:1][CH2:2][C@H:3]([NH:5][C:6]1[C:7]2[S:24][C:23](=[O:25])[NH:22][C:8]=2[N:9]=[C:10]([S:12][CH2:15][C:16]2[S:26][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:4]
Reactant: SCc1cccs1
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2ccccc2)nc2[nH]c(=O)sc12
Product: C[C@H](CO)Nc1nc(SCc2cccs2)nc2[nH]c(=O)sc12
Yield: 3 %

Procedure:
The title compound was prepared by the method described in example 16 step b) from the product of example 15 step e) (0.300 g, 0.79 mmol) and 2-thiophenemethanethiol (0.32 ml, 3.9 mmol).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]([C:29]1[NH:33][C:32]2[CH:34]=[CH:35][C:36]([C:38]#[N:39])=[CH:37][C:31]=2[N:30]=1)([OH:28])[C:4]1[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][C:10]([CH3:17])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2S(C1C=CC(C)=CC=1)(=O)=O.[O-]CC.[Na+]>CCO>[F:41][C:2]([F:1])([F:40])[C:3]([C:29]1[NH:33][C:32]2[CH:34]=[CH:35][C:36]([C:38]#[N:39])=[CH:37][C:31]=2[N:30]=1)([OH:28])[C:4]1[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][C:10]([CH3:17])=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(O)(c4nc5cc(C#N)ccc5[nH]4)C(F)(F)F)c(S(C)(=O)=O)cc(C)c32)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(S(C)(=O)=O)c(C(O)(c2nc3cc(C#N)ccc3[nH]2)C(F)(F)F)c2cc[nH]c12
Temperature: 60 °C

Procedure:
To a solution of 2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (187 mg, 0.310 mmol) in EtOH (3103 μL) was added sodium ethoxide (21% in EtOH, 2.3 mL, 6.21 mmol) and the mixture was stirred at 60° C. After 2 hours the reaction was cooled to room temperature and stirred overnight. The mixture was concentrated and then purified directly by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.64-12.79 (m, 1H) 11.60 (br. s., 1H) 8.38-8.49 (m) 8.05 (s, 1H) 7.97-8.03 (m) 7.89 (m) 7.58-7.66 (m, 1H) 7.48-7.55 (m) 7.18-7.32 (m, 1H) 5.61 (br. s., 1H) 3.52 (s, 3H) 2.57 (s, 3H). HRMS calcd. for C20H16F3N4O3S (M+H)+ 449.0895. found 449.0889.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].CS(O[CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)(=O)=O.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:27][O:26][C:23]1[N:22]=[CH:21][C:20]([CH2:19][N:11]2[C:12]3[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=3)[CH:9]=[CH:10]2)=[CH:25][CH:24]=1
Reactant: COc1ccc(COS(C)(=O)=O)cn1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2ccn(Cc3ccc(OC)nc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 1H-indole-6-carboxylic acid methyl ester (0.54 g, 3.1 mmol) and (6-methoxypyridin-3-yl)methyl methanesulfonate (0.73 g, 3.4 mmol) in DMF (15 mL) was added NaH (0.9 g, 3.7 mmol). After stirring at room temperature for 1 hr, the solution was diluted with ethyl acetate (100 ml) and washed with water (100 ml). The organic layer was dried (MgSO4), filtered and concentrated. The remaining residue was subjected to flash chromatography (40% ethyl acetate/hexane) to provide 0.68 g (75%) of methyl 1-((6-methoxypyridin-3-yl)methyl)-1H-indole-6-carboxylate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:11]>O1CCOCC1>[NH2:11][C:6]1[C:7]([C:8]#[N:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N#Cc1c(Cl)ncnc1Cl
Reactant: N
Solvent: C1COCCO1
Product: N#Cc1c(N)ncnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
4,6-Dichloropyrimidine-5-carbonitrile (4.8 g, 27.59 mols) was suspended in 30 mL dioxane and the mixture was cooled at 0° C. in an ice bath. Ammonia solution (7N in methanol, 20 mL, 140 mmol) was added dropwise over 20 min. The mixture was stirred at 0° C. for 30 min. The solvent was evaporated and the crude was re-dissolved in tetrahydrofuran. A precipite was formed and filtered and washed with more tetrahydrofuran. The organics were evaporated under reduced pressure. The residue was purified using a SP1® Purification System (20%-80%, hexane-ethyl acetate) to give 2.38 g (56% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=3[CH:12]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[N:11]([CH2:28][CH:29]3[CH2:33][CH2:32][O:31][CH2:30]3)[C:10]2=[O:34])[CH:6]=[CH:7][CH:8]=1.ClCC1C=[CH:43][N:42](C)[C:41](=O)C=1>>[F:1][C:2]([F:35])([F:36])[C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=3[CH:12]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)[N:11]([CH2:28][C:29]3[CH:30]=[CH:41][N:42]([CH3:43])[C:32](=[O:31])[CH:33]=3)[C:10]2=[O:34])[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC2CCOC2)cc1
Reactant: Cn1ccc(CCl)cc1=O
Product: Cn1ccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C3=C(C(=O)CCC3)C2c2ccc(C#N)cc2)cc1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound is prepared in analogy to 4-(1-(3-(trifluoromethyl)phenyl)-2,5-dioxo-3-((tetrahydrofuran-3-yl)methyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)benzonitrile (example 25), using 4-(chloromethyl)-1-methylpyridin-2(1H)-one as alkylating agent and stirring the reaction mixture at room temperature for 24 h. Yield: 60 mg; ESI mass spectrum [M+H]+=533; Retention time HPLC: 0.84 min (Z011_S03).
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].Cl.[CH2:7]([O:9][C:10](=[O:14])[CH2:11][CH2:12][NH2:13])[CH3:8].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:7]([O:9][C:10](=[O:14])[CH2:11][CH2:12][NH:13][CH2:2][C:3](=[O:4])[NH2:5])[CH3:8]
Reactant: CCOC(=O)CCN
Reactant: NC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCNCC(N)=O
Temperature: 90 °C
Yield: 51.4 %

Procedure:
A suspension of 2-chloroacetamide (2.34 g, 25.0 mmol), β-alanine ethyl ester hydrochloride (15.36 g, 100 mmol) and K2CO3 (42.0 g) in dry DMF (200 mL) was heated at 90° C. for 24 hours. After cooling to room temperature the reaction mixture was filtered to remove any unreacted β-alanine ethyl ester and the solvent and was removed by distillation under reduced pressure (50° C., 1 Torr). The resulting yellow oil (6.0 g) was purified by silica gel flash column chromatography using ethyl acetate, ethyl acetate/ethanol (2:1, v/v), and finally ethanol as the eluent, to give 2.24 g (50%) of the title compound as a colorless oil. TLC (methanol, det. ninhydrin, Rf=0.65). 1H NMR (DMSO-d6) δ1.18 (t, J=7.1 Hz, 3H, CH3), 2.42, 2.70 (2t, J=6.7 Hz, 4H, CH2CH2), 3.03 (s, 2H, CH2), 4.06 (q, J=7.1 Hz, 2H, OCH2), 7.02, 7.24 (2s (br), 2H, NH2) ppm. 13C NMR (DMSO) δ14.1 (CH3), 34.5 (CH2CO), 44.7 (NCH2CH2), 51.8 (NCH2CN), 59.8 (OCH2), 172.1 (C═O), 173.5 (C═O) ppm. FAB-MS: m/z 175.1 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:44]=[CH:45][CH:46]=1)[CH2:34]B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[CH2:34][C:33]1[CH:44]=[CH:45][CH:46]=[C:31]([O:30][CH3:29])[CH:32]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: COc1cccc(CB2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cccc(Cc2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Yield: 25.5 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (250 mg, 0.57 mmol) was treated with 2-(3-methoxybenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (211 mg, 0.85 mmol), sodium carbonate (2M, 1.28 mL, 2.56 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (70 mg, 0.09 mmol) according to the method described in Example 3 to give 70 mg (26% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:12])=[CH:5][C:6]=1[CH2:7][CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([Cl:12])=[C:5]2[C:9](=[O:11])[CH2:8][CH2:7][C:6]=12
Reactant: O=C(O)CCc1cc(Cl)sc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2c(Cl)sc(Cl)c21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.2 %

Procedure:
To a stirred solution of 3-(2,5-dichloro-3-thienyl)propanoic acid (5.0 g, 24.2 mmol) in CH2Cl2 (50 mL) was added oxalyl chloride (3.5 g, 27.5 mmol) and the mixture was heated at reflux temperature for 1 hour. After cooling, volatiles were removed by evaporation. To a stirred solution of the acid chloride in CH2Cl2 (125 mL) was added aluminum chloride (4.0 g, 30 mmol) at room temperature. After stirring for 20 min, aluminum chloride (4.5 g, 33.7 mmol) was added. The mixture was stirred for additional 1 hour at room temperature. The reaction mixture was poured into ice-water and the whole extracted with dichloromethane (100 mL×3). The combined organic layer was washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to give the subtitle compound as light yellow solids (4.52 g, 98% yield). The compound was used for next reaction without further purification.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:18])[C@@H:6]([NH2:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:3].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH2:2]([O:4][C:5](=[O:18])[C@@H:6]([NH:17][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:3]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
(S)-Ethyl-2-amino-3-(4-nitrophenyl)propionate hydrochloride (1.23 g, 4.47 mmol) was suspended in dichloromethane (25 mL) and to this suspension was added benzoyl chloride (0.628 g, 4.47 mmol) and triethylamine (1.36 g, 13.4 mmol). The mixture was stirred overnight at room temperature under nitrogen. The crude reaction was washed with 5% HCl, water, brine, dried (Na2SO4), concentrated and purified by flash chromatography (silica gel, 2:1 hexanes:EtOAc) to afford the title compound as a white powder (0.865 g, 57%): MS(ES+) m/e 343 [M+H]; mp 99-101° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)O1>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=3)[S:8][C:6]=2[N:7]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Product: Nc1ccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)cn1

Procedure:
4-(5-Chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18 was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A to give crude 5-(5-chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)pyridin-2-amine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A again to give 127 after purification by reverse HPLC. MS (Q1) 408 (M+)
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl.[N:30]1([CH2:37][CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:43]([C:44](O)=O)=[CH:42][N:41]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[N:30]1([CH2:37][CH2:38][O:39][C:40]2[N:41]=[CH:42][C:43]([CH2:44][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:47][CH:48]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)nc1
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)nc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 41.4 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and 6-(2-azepan-1-ylethoxy)nicotinic acid hydrochloride (120 mg) according to an analogous synthetic method to Example 337 described below, the title compound (23 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7](Br)[O:6]1)=[O:4].[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[OH:33])[CH:28]=[O:29]>>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7]([O:33][C:32]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][C:25]=2[F:24])[O:6]1)=[O:4]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: COC(=O)[C@H]1O[C@@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: COC(=O)[C@H]1O[C@@H](Oc2ccc(C=O)cc2F)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 81.3 %

Procedure:
14.2 g (35.8 mmol) of (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-bromo-tetrahydro-pyran-2-carboxylic acid methyl ester is reacted analogously to Example LE1a with 5.05 g of 3-fluoro-4-hydroxybenzaldehyde, and after working-up and purification, 13.3 g (29.1 mmol, 81%) of the title compound is isolated.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[NH:9][C:10]3[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24]Br>CC(O)=O>[C:18]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[NH:9][C:10]3[C:16]([Br:24])=[C:15]([NH2:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc2nc(C(c3ccccc3)c3ccccc3)[nH]c2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1ccc2nc(C(c3ccccc3)c3ccccc3)[nH]c2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of 1.1 g (3.7 mmol) of 2-diphenylmethyl-5-aminobenzimidazole in 50 ml of AcOH was added 0.07 ml (1.3 mmol) of Br2 dropwise and resulting reaction mixture was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo and purified on silica gel column chromatography (5% MeOH/EtOAC) to yield 0.42 g (1.1 mmol, 86%) of the desired product.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[NH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1>>[N:5]1([CH2:3][CH2:2][C:1]#[N:4])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C1CCNC1
Reactant: C=CC#N
Product: N#CCCN1CCCC1
Reaction time: 2 h

Procedure:
At 20 to 30° C., 5.31 g of acrylonitrile was added to 7.11 g of pyrrolidine, which was stirred for 2 hours. Purification by vacuum distillation yielded 1-pyrrolidine-propiononitrile.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH:51]1[CH2:56][CH2:55][CH:54]([O:57][C:58]2[CH:59]=[N:60][CH:61]=[C:62]([C:64]([F:67])([F:66])[F:65])[CH:63]=2)[CH2:53][CH2:52]1>CN(C=O)C.O>[O:27]=[C:25]([N:51]1[CH2:52][CH2:53][CH:54]([O:57][C:58]2[CH:59]=[N:60][CH:61]=[C:62]([C:64]([F:66])([F:65])[F:67])[CH:63]=2)[CH2:55][CH2:56]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:20][N:19]=1)=[O:22]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: FC(F)(F)c1cncc(OC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cncc(C(F)(F)F)c2)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 45.9 %

Procedure:
DIPEA (140 mg, 1.1 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (87 mg, 0.35 mmol) in DMF (2 mL) followed by HOBt (47 mg, 0.35 mmol) and EDCI.HCl (73 mg, 0.38 mmol). After 2 minutes 3-(piperidin-4-yloxy)-5-trifluoromethyl-pyridine hydrochloride (100 mg, 0.35 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, the solid was collected. Purification of the solid by washing with 10% MeOH in CHCl3 afforded 76 mg (47.5% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(5-trifluoromethyl-pyridin-3-yloxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 474, 99%. 1H NMR (300 MHz, DMSO-d6): δ 13.8 (m, 1H), 8.68 (m, 1H), 8.58 (s, 1H), 8.1 (m, 1H), 7.9 (m, 1H), 7.8 (m, 2H), 7.4 (m, 4H), 7.1 (m, 1H), 5.0 (m, 1H), 4.2 (m, 2H), 4.0 (m, 1H), 3.8 (m, 1H), 3.4 (m, 1H), 3.3 (m, 1H), 2.0 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22](Br)[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)C.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:22]2[CH:23]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:25]=[C:20]([S:17]([N:15]([CH3:16])[C@@H:10]3[CH2:11][CH2:12][CH2:13][C:14]4[N:6]([CH2:5][C:4]([OH:3])=[O:31])[N:7]=[CH:8][C:9]3=4)(=[O:18])=[O:19])[CH:21]=2)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Product: CN([C@@H]1CCCc2c1cnn2CC(=O)O)S(=O)(=O)c1cc(-c2ccc(F)cc2)cc(C(F)(F)F)c1
Yield: 42 %

Procedure:
Starting with {(R)-4-[(3-bromo-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (prepared by the method analogous to the one described for example 9-1, 1st step) and 4-fluoro-phenylboronic acid, using a method analogous to the one described for example 10-1, {(R)-4-[(4′-fluoro-5-trifluoromethyl-biphenyl-3-sulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid (5 mg, 42%) was obtained. MS cald. for C25H25F4N3O4S 539, obsd. (ESI+) [(M+H)+] 540.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11]CC(C)=C)=[CH:7][CH:6]=1)[CH3:2].[OH-].[Na+]>CN1CCCC1=O>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[C:9]([CH2:6][C:5]([CH3:10])=[CH2:4])[CH:10]=1)[CH3:2]
Reactant: C=C(C)COc1ccc(C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: C=C(C)Cc1cc(C(=O)OCC)ccc1O
Temperature: 25 °C

Procedure:
A mixture of 4-(2-methylprop-2-enyloxy)benzoic acid ethyl ester (15 g) and 1-methyl-2-pyrrolidinone (150 mL) is heated at reflux for nine hours. The reaction mixture is cooled to room temperature and made basic (pH ˜10) by using aqueous sodium hydroxide solution. The aqueous layer is washed with toluene (2×20 mL) and then made acidic (pH ˜2) with 2N HCl. The aqueous layer is extracted with ethyl acetate (3×20 mL). Combined organic layers are washed with brine (1×15 mL) and dried over sodium sulphate. Removal of solvent gives a dark brown liquid which is purified by column chromatography (silica gel 230-400 mesh, n-hexane:ethyl acetate, 80:20) to give 4-hydroxy-3-(2-methylprop-2-enyl)benzoic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[C:12](=[O:13])[O:11]C(C)(C)[O:9][C:8]2=[O:16])=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([C:8]([OH:16])=[O:9])[C:12]([OH:13])=[O:11])=[CH:17][CH:18]=1
Reactant: CC1(C)OC(=O)C(Cc2ccc(Cl)cc2)C(=O)O1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(Cc1ccc(Cl)cc1)C(=O)O

Procedure:
A solution of 5-(4-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.50 g, 5.58 mmol, Intermediate 3: step a) and 3 M aqueous NaOH (16 mL) was heated in the microwave at 75 W for 20 minutes at 120° C. The aqueous mixture was extracted with EtOAc (1×) then acidified to pH 1 with concentrated aqueous HCl and extracted with EtOAc (2×). The combined EtOAc extract was washed with H2O, brine and dried over Na2SO4, filtered. Solvents were removed under reduced pressure to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]([CH3:11])=[CH:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:14]=1[CH:15]=O.[CH3:22][O:23][C:24]([CH2:26][C:27]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=O)=[O:25]>CO>[C:7]([O:6][C:4]([C:3]1[CH:15]([C:14]2[C:13]([Cl:12])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:21])[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:27]([CH2:26][C:24]([O:23][CH3:22])=[O:25])[NH:1][C:2]=1[CH3:11])=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(N)=CC(=O)OC(C)(C)C
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: O=Cc1c(Cl)cccc1Cl
Solvent: CO
Product: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC(C)(C)C)=C(C)N1
Yield: 10.1 %

Procedure:
A mixture of t-butyl 3-amino-2-butenoate (3.911 g, 24.8 mmol), 2,6-dichlorobenzaldehyde (4.354 g, 24.8 mmol), and dimethyl acetonedicarboxylate (3.657 ml, 24.8 mmol) in methanol (50 ml) was refluxed for 45 h. The solvent was evaporated and the residue was chromatographed on 800 g silica gel (dichloromethane/ethyl acetate: 23/2 as eluent) to give 1.18 g of product. On silica GF plates, the product was blue fluorescent at Rf=0.3.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH2:25]([O:10][C:9](=[O:11])[CH2:8][C:3]([CH2:2][C:1]([OH:13])=[O:12])([C:5]([OH:7])=[O:6])[OH:4])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CCCCCCCCCCCCOC(=O)CC(O)(CC(=O)O)C(=O)O

Procedure:
A blend of citric acid (63 grams, 0.3 mole), dodecyl alcohol (55.8 grams, 0.31 mole), p-toluene sulfonic acid (0.1 gram, 0.6 mole) and 300 ml. of dioxane was refluxed for 72 hours, passing the condensed vapor through 4A molecular sieve. The dioxane solvent was then evaporated under reduced pressure (30 mm.) to a 150 gram residue. This mixture was diluted with 200 ml. of toluene and the reaction mixture subsequently stripped to 60° C. at 5 mm. pressure. The residue was an amber oil which solidified to a cream colored soft solid, weight 106.6 grams (Theory 108 grams).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][S:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Cl)(=[O:30])=[O:29]>C(N(C(C)C)C(C)C)C>[OH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][S:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)(=[O:30])=[O:29]
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCl)NCCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NCCCCO
Yield: 91.7 %

Procedure:
1-[Bis(4-fluorophenyl)methyl]piperazine (576.7 mg, 2.00 mmol) and N-(4-hydroxybutyl)-5-chloropentanesulfonamide (515.6 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(4-hydroxybutyl)-5-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]pentanesulfonamide (934.3 mg) as a pale yellow oil (91.7%).