Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[S:6][CH2:5][CH2:4]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CO.C([BH3-])#N.[Na+]>[CH2:16]([NH:1][CH2:2][CH:3]1[C:15]2[C:7](=[N:8][C:9]3[C:14]=2[CH2:13][CH:12]=[CH:11][CH:10]=3)[S:6][CH2:5][CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCC1CCSc2[nH]c3ccccc3c21
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: C1=CCC2=C3C(=NC2=C1)SCCC3CNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of 4-aminomethyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (150 mg) in methanol (5 ml) are added a solution of benzaldehyde (76 mg) in methanol (1.5 ml) and sodium cyanoborohydride (132 mg). The mixture is adjusted to pH 7 with a solution of hydrochloride in methanol, stirred at room temperature for 1 hour and evaporated to remove the solvent. The residue is dissolved in ether, washed with a 10% aqueous solution of sodium hydroxide and a saline solution, dried and evaporated to give the title compound (210 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH2:9][CH3:10])=[N:6][CH:7]=1.[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=O)=[CH:18][CH:17]=1>>[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:8]([C:5]2[N:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:9][CH3:10])=[CH:18][CH:17]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Reactant: CCC(=O)c1ccc(O)cn1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc(O)cn1

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, 1-(5-hydroxypyridin-2-yl)propan-1-one (0.15 g, 1.0 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (0.549 g, 2.0 eq) to give the desired product (Z/E=1/1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[C:22](=O)[CH:21]2[CH:16]([CH2:17][NH:18][CH2:19][CH2:20]2)[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[CH2:22][CH:21]2[CH:16]([CH2:17][NH:18][CH2:19][CH2:20]2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C2CCNCC2C(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CC3CCNCC3C2)cc1
Temperature: 25 °C
Yield: 25.4 %

Procedure:
To a solution of LiAlH4 (1.00 g) in THF was added slowly 2-benzylhexahydro-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione (2.00 g) at 0° C. The reaction mixture was refluxed for 6 h under N2, and cooled to rt, quenched with ice-water and filtered. The filtrate was concentrated in vacuo to give the title compound as yellow oil (0.45 g, 25%). The crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 217.2 (M+1).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)(=O)=O.C1COCC1.[CH3:29][NH:30][CH3:31]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:7][CH2:6][N:30]([CH3:31])[CH3:29])=[CH:10][CH:11]=1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)NC(CCOS(C)(=O)=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Product: CN(C)CCC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 150 °C
Yield: 84 %

Procedure:
3-(tert-Butoxycarbonylamino)-3-(4-chlorophenyl)propyl methanesulfonate (Intermediate 31) (0.075 g, 0.21 mmol) and tetrabutylammonium iodide (0.015 g, 0.04 mmol) were dissolved in a solution of dimethylamine in THF (2M, 5.153 mL, 10.31 mmol) and sealed into a microwave tube. The reaction was heated to 150° C. for 30 minutes in the microwave reactor and cooled to ambient temperature. The reaction mixture was concentrated, diluted with DCM (25 mL) and washed with water (25 mL). The organic layer was filtered through a phase-separating filter paper and evaporated. The crude product was purified by flash silica chromatography, elution gradient 4 to 8% (10:1 MeOH/conc. NH3 (aq)) in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 1-(4-chlorophenyl)-3-(dimethylamino)propylcarbamate (0.054 mg, 84%) as a colourless oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[O:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([OH:30])[C@H:21]([NH:24][C:25](=[O:29])[CH:26]([Cl:28])[Cl:27])[CH2:22][F:23])=[CH:16][CH:15]=2)=[CH:12][N:13]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[O:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([OH:30])[C@H:21]([NH:24][C:25](=[O:29])[CH:26]([Cl:27])[Cl:28])[CH2:22][F:23])=[CH:16][CH:15]=2)=[CH:12][N:13]=1
Reactant: CC(C)(C)OC(=O)NCc1ncc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ncc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.8 %

Procedure:
To a stirred solution of (5-{4-[(1R,2S)-2-(2,2-Dichloro-acetylamino)-3-fluoro-1-hydroxy-propyl]-phenyl}-oxazol-2-ylmethyl)-carbamic acid tert-butyl ester (0.006 g, 0.012 mmol) in CH2Cl2 (1.0 mL) is added trifluoroacetic acid (0.1 mL) at 0° C. and stirred at room temperature for 2 hours. Reaction mixture is concentrated in vacuum and the residue is washed with n-pentane dried under vacuum to give the title compound (0.005 g). 1H-NMR (400 MHz, DMSO-d6) δ: 4.22-4.28 (m, 1.5H), 4.31 (s, 2H), 4.40-4.44 (m, 0.5H), 4.56-4.60 (m, 0.5H), 4.68-4.71 (m, 0.5H), 4.89 (m, 1H), 6.02 (d, J=4.28 Hz, 1H), 6.49 (s, 1H), 7.47 (d, J=8.16 Hz, 2H), 7.67 (d, J=8.2 Hz, 2H), 7.72 (s, 1H), 8.21 (bs, 3H), 8.60 (d, J=8.88 Hz, 1H). LC-MS (m/z): [M+H]=376.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9](Br)[CH3:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH:16]([C:18](=[S:22])[O:19]CC)[NH2:17]>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:10])[S:22][C:18](=[O:19])[NH:16][N:17]=2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(Br)C(=O)c1ccc(N)c([N+](=O)[O-])c1
Reactant: CCOC(=S)NN
Solvent: CC#N
Product: CC1SC(=O)NN=C1c1ccc(N)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
36.5 g (134 mM) of 1-(4-amino-3-nitrophenyl)-2-bromopropan-1-one and 24.3 g (202.5 mM) of O-ethyl hydrazinecarbothioate dissolved in 190 ml of acetonitrile are refluxed for 4 hours with stirring. The reaction mixture is cooled and maintained at 0° C. for 16 hours. The crystalline solid is filtered off and washed with cold acetonitrile to give, after drying, 10.4 g of 5-(4-amino-3-nitrophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one in the form of a solid.
Reaction SMILES: [CH2:1]([C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH:9]1[OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:1]([C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH:9]1[O:13][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([CH3:25])=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCCC1O
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1(Cc2ccccc2)CCCC1OC(=O)c1ccc(C)cc1

Procedure:
7.44 grams of 2-benzyl-2-ethoxycarbonyl-cyclopentanol obtained in Example 14 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 3.66 ml of pyridine was slowly added, then 6.12 ml of 4-methyl benzoyl chloride was dropwise added. Upon the completion of the addition, the reaction was continued under reflux condition for 12 hours. Then the procedure as described in Example 23 was followed, to give 12.53 g of yellow liquid. MS: m/e 367(M++1), 366(M+), 364(M+−2), 293(M+—CO2CH2CH3), 247(M+—CH3C6H4CO), 231(M+—CH3C6H4CO2), 201, 184, 156, 139, 119 (base), 91, 77.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([SH:11])[S:9][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:11][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(S)n1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCSc1nc(C(=O)OCC)cs1
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a solution of 2-mercaptothiazole-4-carboxylic acid ethyl ester (Zhelyazkov, L.; Todorova, N.; Manolova, P. Tr. Nauchnoizsled. Khim.-Farm. Inst., 9, 59-67 (1974); Chem. Abstr., 83, 58706 q) (3.0 g) in DMF (20 ml) is added sodium hydride (0.70 g of 60% dispersion). After 10 min, 1-bromooctane (3.0 ml) is added, and the mixture is stirred at 60° for 30 min. The mixture is poured into water and extracted with ether, and the extracts are dried, filtered, and concentrated. The residue is recrystallized from hexane to provide 2-(octylthio)thiazole-4-carboxylic acid ethyl ester as a colorless solid (3.7 g, 78%). This material is reduced in the usual fashion with lithium aluminum hydride in THF, providing 2-(octylthio)thiazole-4-methanol (2.12 g, 67%) as a colorless oil after chromatography. This is combined with DDQ (1.8 g) in 1,4-dioxane (25 ml) and stirred for 48 hr at room temperature. The reaction mixture is filtered, and the filtrate is concentrated and chromatographed with dichloromethane to provide 2-(octylthio)thiazole-4-carboxaldehyde as a tan solid (1.67 g, 81%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:36])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:35])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[S:25]([C:22]1[CH:21]=[CH:20][C:19]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:35])[CH:14]=3)[CH:9]=[C:8]([CH2:7][C:6]([OH:36])=[O:5])[C:17]=2[CH3:18])=[CH:24][CH:23]=1)(=[O:26])=[O:27]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3ccccc3Cl)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
Lithium hydroxide monohydrate (0.016 g, 0.38 mmol) was added to a stirred solution of {4-[4-(2-chloro-benzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.045 g, 0.09 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure. The crude residue was diluted with water, and acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(2-chloro-benzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.031 g, 71%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.42-12.50 (m, 1 H), 8.37-8.41 (m, 1 H), 8.08 (d, J=7.80 Hz, 2 H), 8.01 (dd, J=8.80, 6.40 Hz, 1 H), 7.91 (s, 1 H), 7.70-7.82 (m, 4 H), 7.53 (d, J=7.80 Hz, 2 H), 7.35-7.41 (m, 1 H), 6.62 (dd, J=11.00, 2.60 Hz, 1 H), 3.84 (s, 2 H), 2.05 (s, 3 H). MS calcd. for C25H17ClFO4S [(M−H)−] 467, obsd. 467.3.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:19])[N:30]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14](=[O:15])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:21][CH3:22]
Reactant: NCc1ccccc1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccccc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.3 g, 1.0 mmol) was treated with benzylamine (0.44 mL, 4.0 mmol). Purification on silica gel, eluting with 3:1 hexane/acetone, afforded a solid that was converted to an HCl salt and recrystallized from EtOAc/2-propanol to give 124 as a white solid (m.p. 247-248° C.).
Reaction SMILES: [C:1]([C:8]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:9]=1[C:10]([O:12]C)=O)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[CH3:21][NH:22][O:23][CH3:24].[Li]CCCC>>[C:1]([C:8]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:9]=1[C:10]([N:22]([CH3:21])[O:23][CH3:24])=[O:12])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC#Cc1cc(OC)ccc1C(=O)OC
Reactant: CNOC
Agent: Cl
Agent: [Li]CCCC
Product: CCCCCC#Cc1cc(OC)ccc1C(=O)N(C)OC
Yield: 78 %

Procedure:
Treatment of methyl 2-(1-heptyn-1-yl)-4-(methyloxy)benzoate (110) (0.67 g, 2.57 mmol) with a mixture of N,O-dimethylhydroxylamine hydrochloride and nBuLi gave 0.58 g (78%) of the title compound (111) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 0.93 (t, J=7.0 Hz, 3H), 1.30-1.50 (m, 4H), 1.60-1.70 (m, 2H), 2.41 (t, J=7.1 Hz, 2H), 3.31 (br s, 3H), 3.64 (br s, 3H), 3.83 (s, 3H), 6.86 (dd, J1=8.5 Hz, J2=2.5 Hz, 1H), 6.96 (d, J=2.6 Hz, 1H), 7.27 (d, J=8.6 Hz, 1H). LCMS (ESI): m/z 290 (M+H)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[C:10]([Br:11])=[CH:9][C:8]([Br:12])=[CH:7][N:6]=1>O>[Br:11][C:10]1[C:5]([O:2][CH3:1])=[N:6][CH:7]=[C:8]([Br:12])[CH:9]=1
Reactant: C[O-]
Reactant: Brc1cnc(Br)c(Br)c1
Agent: [Na+]
Solvent: O
Product: COc1ncc(Br)cc1Br
Temperature: 50 °C
Reaction time: 2 h

Procedure:
80 ml of a 28% sodium methoxide solution was incorporated with 30.0 g of 2,3,5-tribromopyridine under ice-cooling, followed by stirring at 50° C. for 2 hours. The reaction solution was diluted with water and extracted with diethyl ether. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane=1:20), to give 18.5 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.C(O)C.Cl[CH:16]([CH3:20])[C:17](=O)[CH3:18]>CCOCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[S:8][C:16]([CH3:20])=[C:17]([CH3:18])[N:9]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)C(C)Cl
Reactant: COc1ccc(C(N)=S)cc1
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(-c2nc(C)c(C)s2)cc1
Yield: 87.3 %

Procedure:
To a stirred mixture of 65.1 g (4-methoxy)thiobenzamide and 156 ml ethanol was added dropwise 50.1 g 3-chloro-2-butanone, and the reaction mixture was heated at reflux for 3 hours. An additional 6.1 g 2-chloro-3-butanone was added and heating was continued for an additional hour. The reaction mixture was cooled, 300 ml ether added, and the solid which precipitated was collected and dried to give 74.5 g 2-(4-methoxyphenyl)-4,5-dimethylthiazole in the form of its hydrochloride monohydrate, m.p. 166°-170° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:11])[CH:6]([Cl:10])[C:7]([CH3:9])=[O:8].C([Li])CCC.[CH:17]1([C:22](=[O:27])[CH2:23][CH2:24][C:25]#[CH:26])[CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1>[CH3:3][O:4][C:5](=[O:11])[CH:6]([Cl:10])[C:7](=[O:8])[CH2:9][C:22]([CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)([OH:27])[CH2:23][CH2:24][C:25]#[CH:26]
Reactant: C#CCCC(=O)C1CCCC1
Reactant: COC(=O)C(Cl)C(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCC(O)(CC(=O)C(Cl)C(=O)OC)C1CCCC1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
A slurry of NaH (3.2 g, 60% suspension in mineral oil, 80 mmol) in dry THF (250 mL) was cooled to −40° C. Methyl-2-chloroacetoacetate (9.74 mL, 80 mmol) was added slowly. The reaction was stirred until all gas evolution had ceased, and then butyl lithium (2.5 M, 32 mL, 80 mmol) was added. The reaction was stirred for 10 minutes, and then 1-cyclopentyl-pent-4-yn-1-one (4.0 g, 27 mmol) from Step 2 above, was added as a solution in 20 mL THF. The reaction was stirred 1 hour, and then warmed to room temperature. The reaction was quenched with 1 N HCl (200 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 and the organic layers were combined. The organic layer was washed with water, and then concentrated by rotary evaporation. The crude product was purified by chromatography to yield the pure product (6.345 g, 78% yield).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.CO[CH:14](OC)[CH2:15][NH:16][C:17](=[O:41])[C@@H:18]([NH:27][S:28]([C:31]1[C:36]([CH3:37])=[CH:35][C:34]([O:38][CH3:39])=[CH:33][C:32]=1[CH3:40])(=[O:30])=[O:29])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>O1CCOCC1>[CH3:39][O:38][C:34]1[CH:35]=[C:36]([CH3:37])[C:31]([S:28]([N:27]2[CH:14]=[CH:15][NH:16][C:17](=[O:41])[C@@H:18]2[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=[O:30])=[O:29])=[C:32]([CH3:40])[CH:33]=1
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)NCC(OC)OC)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: COc1cc(C)c(S(=O)(=O)N2C=CNC(=O)[C@@H]2CC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
PTSA (0.62 eq) was added to a solution of (S)-tert-butyl 4-(2,2-dimethoxyethylamino)-3-(4-methoxy-2,6-dimethylphenylsulfonamido)-4-oxobutanoate (1.26 mmol) in dioxane (12 ml) and the mixture was stirred for 16 h at room temperature. The solvent was removed under vacuum and the residue taken up in ethyl acetate. The organic phase was extracted with water and saturated sodium chloride solution, dried (Na2SO4) and concentrated to small volume under vacuum. The crude product was processed by column chromatography. Yield: 35%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7](=[O:9])[CH3:8])[S:5][CH:6]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:7](=[O:9])[CH:8]=[CH:12][N:13]([CH3:15])[CH3:14])[S:5][CH:6]=1
Reactant: CC(=O)c1cc(Cl)cs1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1cc(Cl)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
A mixture of 1-(4-chloro-2-thienyl)ethanone (32.1 mmol) and N,N-dimethylformamide dimethyl acetal (112.2 mmol) was refluxed for 3 h and then allowed to cool to room temperature whereupon crystallization occurred. The reaction mixture was stored in a freezer at −18° C. for 2 h. The supernatant liquid was decanted, the crystals were dried in vacuum to afford 5.3 g (77% yield) of 1-(4-chloro-2-thienyl)-3-(dimethylamino)prop-2-en-1-one which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11](Cl)[N:10]=[C:9]([N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)[N:8]=1.[N:30]1[CH:31]=[CH:32][N:33]2[CH2:38][CH2:37][NH:36][CH2:35][C:34]=12.C(=O)([O-])O.[Na+]>CN(C)C(=O)C.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:36]2[CH2:37][CH2:38][N:33]3[CH:32]=[CH:31][N:30]=[C:34]3[CH2:35]2)[N:10]=[C:9]([N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)[N:8]=1
Reactant: COC(=O)c1c(Cl)nc(N2CCC(O)CC2)nc1NCc1ccc(OC)c(Cl)c1
Reactant: c1cn2c(n1)CNCC2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(N2CCC(O)CC2)nc1N1CCn2ccnc2C1
Reaction time: 5 h

Procedure:
To a solution of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-chloro-2-(4-hydroxypiperidin-1-yl)pyrimidine (prepared in the above (3)) 56 mg in N,N-dimethylacetamide 0.5 ml are added a solution of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 31 mg in N,N-dimethylacetamide 0.5 ml and triethylamine 27 μl at room temperature, and the mixture is stirred at 80–90° C. for 5 hours. The reaction mixture is diluted with an aqueous citric acid solution, made basic with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-2-(4-hydroxypiperidin-1-yl)pyrimidine as a pale yellow powder, 66 mg.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]1.F[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>C(#N)C>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]2)=[N:11][CH:12]=1
Reactant: Fc1ccc(F)nc1
Reactant: OCCc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: OCCc1cnn(-c2ccc(F)cn2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
To a solution of 2-(1H-pyrazol-4-yl)ethanol (1.0 g, 8.9 mmol) and 2,5-difluoropyridine (0.89 mL, 9.8 mmol) in acetonitrile (45 mL), Cs2CO3 (9.7 g, 17.8 mmol) was added, and the resulting mixture was stirred for 3 hours at 80° C. The reaction mixture was allowed to cool, then water was added thereto, followed by extraction with EtOAc. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over Na2SO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane/EtOAc=90/10 to 30/70) to obtain the title compound (0.63 g) (colorless solid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:32])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]([O:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:16]=3[O:30][CH3:31])[N:14]=2)[CH:5]=[C:4]([Cl:33])[C:3]=1/[CH:34]=[C:35](\[CH3:41])/[C:36]([O:38]CC)=[O:37].[OH-].[Na+].Cl>C1COCC1.C(O)C>[Cl:33][C:4]1[CH:5]=[C:6]([C:8](=[O:32])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]([O:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:16]=3[O:30][CH3:31])[N:14]=2)[CH:7]=[C:2]([Cl:1])[C:3]=1/[CH:34]=[C:35](\[CH3:41])/[C:36]([OH:38])=[O:37]
Reactant: CCCCCC[C@H](OC)c1cccc(-c2csc(NC(=O)c3cc(Cl)c(/C=C(\C)C(=O)OCC)c(Cl)c3)n2)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCC[C@H](OC)c1cccc(-c2csc(NC(=O)c3cc(Cl)c(/C=C(\C)C(=O)O)c(Cl)c3)n2)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
Ethyl (S)-(E)-3-(2,6-dichloro-4-(4-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylate (14, 6.76 g) obtained in the fifth step was dissolved in THF (20 mL) and ethanol (20 mL), a 4 mol/L sodium hydroxide aqueous solution (13.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized with hydrochloric acid, and extracted with ethyl acetate. The extraction residue was recrystallized with methanol to obtain (S)-(E)-3-(2,6-dichloro-4-(4-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylic acid (C-1B, 5.8 g, yield 88%).