Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[S:10][C:11]2[N:12]([C:32]([C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)=[O:33])[CH:13]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]([CH3:17])[N:16]=2)=CC=1.FC(F)(F)C(O)=O.C(S)C>ClCCl>[CH3:17][C:15]1[NH:16][C:11](=[S:10])[N:12]([C:32]([C:34]2[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=2)=[O:33])[CH:13]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:14]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C1=C(C)N=C(SCc2ccc(OC)cc2)N(C(=O)c2ccc([N+](=O)[O-])cc2)C1c1cccc([N+](=O)[O-])c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCS
Product: CCOC(=O)C1=C(C)NC(=S)N(C(=O)c2ccc([N+](=O)[O-])cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 1.3 g. (0.0022 mole) of 1,6-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-4-methyl-6-(3-nitrophenyl)-1-[(4-nitrophenyl)carbonyl]-5pyrimidinecarboxylic acid, ethyl ester, 0.75 ml. (0.0097 mole) of trifluoroacetic acid and 0.32 g. (0.0050 mole) of ethanethiol in 15 ml. of dichloromethane is stirred at room temperature for 24 hours. The solvent is evaporated and the residue is triturated with isopropyl ether to give 0.95 . g of the title compound as a yellow solid, m.p. 139°-141°. TLC (silica gel; ethyl acetate:hexane, 1:1) Rf =0.35.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:20]([CH3:21])[C:6]2=[N:7][C:8]([S:11][C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=3)=[CH:9][CH:10]=[C:5]2[N:4]=1.S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28]>C(O)(=O)C>[Cl:1][CH2:2][C:3]1[N:20]([CH3:21])[C:6]2=[N:7][C:8]([S:11][C:12]3[CH:13]=[C:14]([CH3:19])[C:15]([N+:27]([O-:29])=[O:28])=[C:16]([CH3:18])[CH:17]=3)=[CH:9][CH:10]=[C:5]2[N:4]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C)cc(Sc2ccc3nc(CCl)n(C)c3n2)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc(Sc2ccc3nc(CCl)n(C)c3n2)cc(C)c1[N+](=O)[O-]
Reaction time: 64 h

Procedure:
To a mixture of 2-chloromethyl-5-(3,5-dimethylphenylthio)-3-methyl-3H-imidazo[4,5-b]pyridine (2.54 g), sulfuric acid (5 ml) and acetic acid (45 ml) was added nitric acid (0.52 ml) in an ice bath. The mixture was allowed to stand at room temperature for 64 hours. The reaction mixture was concentrated, diluted with water, neutralized with sodium bicarbonate and then extracted with ethyl acetate. The extract was concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=1:1 as the eluant to afford the desired compound (0.53 g, mp 133-135° C.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:11]=[C:12]([C:15]([F:18])=[CH:16][CH:17]=1)[CH:13]=[O:14].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:10]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:11][C:12]=1[CH:13]=[O:14]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1cc(-c2ccsc2)ccc1F
Temperature: 80 °C

Procedure:
1.89 g of 3-thiopheneboronic acid (0.015 mol) are added to a solution of 3-bromo-6-fluorobenzaldehyde (2 g, 0.016 mol) in 35 ml of 1,2-dimethoxyethane, followed by addition of aqueous 2N sodium carbonate solution (3.13 g, 0.030 mol) and a catalytic amount of tetrakis(triphenylphosphine)palladium (0.34 g, 2.96 10−4 mol). The reaction mixture is heated at 80° C. for 20 hours and is then cooled to room temperature and poured into water. The resulting mixture is extracted with ethyl acetate and the organic phase is washed with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate and filtered, and the solvent is evaporated off under reduced pressure. The title product is isolated from the black oil obtained by bulb-to-bulb distillation at 150° C. under reduced pressure (4 10−2 mmbar). 1.36 g of a pale yellow oil which solidifies are isolated.
Reaction SMILES: Cl.O1CCOCC1.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[S:22]1[C:26]2[CH:27]=[C:28]([NH:31][C:32]([N:34]3[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH:35]3[CH2:47][O:48][C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)=[O:33])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1>CO>[S:22]1[C:26]2[CH:27]=[C:28]([NH:31][C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH:35]3[CH2:47][O:48][C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)=[O:33])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccc3ncsc3c2)C(COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1ccc2ncsc2c1)N1CCNCC1COc1cccnc1
Reaction time: 8 h
Yield: 85.1 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(benzo[d]thiazol-6-ylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate di-TFA salt (154 mg, 0.221 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure, dissolved in 1 N NaOH, and extracted with EtOAc (3×). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure, yielding 69.5 mg (85%) of the title compound as an off-white solid. LC-MS: RT=3.62 min, [M+H]+=370.1.
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3=[CH:16][C:17]([C:19]([OH:21])=O)=[N:18][N:10]3[C:9](=[O:22])[C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1>CN(C=O)C>[CH2:1]([S:5][C:6]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3=[CH:16][C:17]([C:19]([NH:36][C:37]4[NH:41][N:40]=[N:39][N:38]=4)=[O:21])=[N:18][N:10]3[C:9](=[O:22])[C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSc1ccc2[nH]c3cc(C(=O)O)nn3c(=O)c2c1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCSc1ccc2[nH]c3cc(C(=O)Nc4nnn[nH]4)nn3c(=O)c2c1

Procedure:
From 4,9-dihydro-7-butylthio-9-oxo-pyrazolo-[5,1-b]quinazoline-2-carboxylic acid (1.9 g; 6 mmole), DMF (25 ml), 1,1'-carbonyl-diimidazole (2.19 g; 13.5 mmole) and 5-amino-1H-tetrazole, monohydrate (0.70 g; 6.8 mmole), following the procedure of Example 3, there is obtained 4,9-dihydro-7-butylthio-9-oxo-N-1H-tetrazol-5-yl-pyrazolo[5,1-b]quinazoline-2-carboxamide, with 1H-imidazole (3:1) (0.4 g); mp 285° (d).
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH2:9])=[CH:4][C:3]=1[CH3:13].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH:9][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:4][C:3]=1[CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(OCCN)cc(C)c1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(OCCNS(C)(=O)=O)cc(C)c1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of 2-(4-bromo-3,5-dimethylphenoxy)ethanamine (100 mg) and triethylamine (63 μL) in dichloromethane (2 mL) is added methanesulfonyl chloride (32 μL). The mixture is stirred for 2 hours at 0° C. Then the mixture is partitioned between dichloromethane and water. The organic phase is separated, washed with brine and dried (MgSO4). The solvent is evaporated and the residue is purified by HPLC on reversed phase to give the title compound. Yield: 90 mg; LC (method 7): tR=1.01 min; Mass spectrum (ESI+): m/z=322 [M+H]+.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[C:20]([F:28])[CH:19]=[CH:18][C:17]=1B(O)O>>[F:28][C:20]1[C:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[C:16]([F:15])[CH:17]=[CH:18][C:19]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: OB(O)c1ccc(F)c(-c2ccncc2)c1F
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)c(F)c1-c1ccncc1

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 2,4-difluoro-3-(pyridin-4-yl)benzeneboronic acid as described in Example 65 to give 3-[2,4-difluoro-3-(pyridin-4-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a white solid. Bis-hydrochloride (from ethanol/ethyl acetate): δH (400 MHz, DMSO) 7.60-7.65 (2H, m), 7.96-8.01 (1H, m), 8.16 (2H, d, J 6), 8.34 (1H, s), 9.00-9.02 (2H, m), 9.34 (1H, dd, J 7 and 3); m/z (ES+) 377 (M++H).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)=[CH:17][CH:16]=3)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1C=CC=CC=1>ClCCl>[C:27]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:13]([N:10]3[CH2:11][CH2:12][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:8][CH2:9]3)=[O:14])=[CH:16][CH:17]=2)[S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])=[CH:30][CH:29]=1)#[N:28]
Reactant: N#Cc1ccc(CNc2ccc(C(=O)N3CCN(c4ccccc4)CC3)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(CN(c2ccc(C(=O)N3CCN(c4ccccc4)CC3)cc2)S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 23.5 %

Procedure:
A mixture of 4-{[4-(4-Phenyl-piperazine-1-carbonyl)-phenylamino]-methyl}-benzonitrile (50 mg, 0.13 mmol), phenylsulfonylchloride (80 mg, 0.42 mmol) and pyridine (0.04 mL, 0.44 mmol) in dichloromethane (5 ml) was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature and the quenched by the addition of water (4 ml). The organics were collected, dried over magnesium sulfate and concentrated in vacuo The residue was purified by preparative thin layer chromatography (dichloromethane/ethyl acetate 1:1) to afford the title compound as a white solid (16.4 mg, 27% yield). HPLC retention time 6.71 min. Mass spectrum (ES+) m/z 475 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][S:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]=1)[CH3:2].[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([Cl:32])=[CH:34][CH:35]=3)=[CH:17][C:16]=2[CH2:22][S:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CSCc2ccccc2)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CSCc2ccccc2)c1

Procedure:
As described for Example 10, [3-(2-bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and benzyl mercaptan were reacted to provide [3-(2-benzylsulfanylmethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester, which was reduced to [3-(4-amino-2-benzylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and then treated with 4-chlorobenzoyl chloride to provide {3-[2-benzylsulfanylmethyl-4-(4-chloro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester provided Compound 18.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:8]([CH:9]=O)[C:7]1([CH3:12])[CH3:11])=[O:5])[CH3:2].P(OCC)(OCC)OCC.[Cl:23][C:24](Cl)([Cl:28])C([O-])=O.[Na+].O>COCCOCCOC>[CH2:1]([O:3][C:4]([CH:6]1[CH:8]([CH:9]=[C:24]([Cl:28])[Cl:23])[C:7]1([CH3:12])[CH3:11])=[O:5])[CH3:2]
Reactant: O=C([O-])C(Cl)(Cl)Cl
Reactant: CCOC(=O)C1C(C=O)C1(C)C
Agent: CCOP(OCC)OCC
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Temperature: 150 °C
Yield: 73 %

Procedure:
A mixture of 17.0 g (0.1 mole) of 3-formyl-2,2-dimethyl-cyclopropane-1-carboxylic acid ethyl ester, 16.6 g (0.1 mole) of triethyl phosphite and 18.5 g (0.1 mole) of sodium trichloroacetate in 100 ml of diglyme was heated to 150° C. under argon for 6 hours. The reaction mixture was then poured into water. Extraction with 2 portions of 100 ml each of methylene chloride followed. The combined methylene chloride extracts were dried over sodium sulphate. 3-(2,2-Dichlorovinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid ethyl ester was obtained as a crude product in a yield of 73% of theory.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]([C:9]([OH:11])=[O:10])[N:7]2[C:12](=[O:23])[CH:13]([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C@H:6]2[S:5][CH:4]=1.[C:24](=O)(O)[O-:25].[Na+].C(OCC)(=O)C>CO.C(Cl)(Cl)Cl>[CH3:24][O:25][CH2:2][C:3]1[CH:8]([C:9]([OH:11])=[O:10])[N:7]2[C:12](=[O:23])[CH:13]([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C@H:6]2[S:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)C(CBr)=CS[C@H]12
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COCC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)O
Reaction time: 0.33 h

Procedure:
The benzyl ester of 3-bromomethyl-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid is dissolved in methanol. After standing at room temperature for 20 minutes the reaction mixture is poured into a dilute sodium bicarbonate solution and extracted with methylene chloride. The organic layer is washed with aqueous sodium chloride and dried. Removal of the solvent affords 35 mg. of crude product. The pure benzyl ester of 3-methoxymethyl-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid is then isolated by preparative thin layer chromatography (15% ethyl acetate in chloroform as eluant).
Reaction SMILES: [CH3:1]N(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:46])[CH:12](P(OC)(OC)=O)NC(=O)C1C(C)=CC(N2C(NCC3C=CC=C4C=3C=CN4)=NN=N2)=CC=1C.[CH3:47][C:48]1[S:49][CH2:50][C:51]([CH3:55])(C=O)[N:52]=1>O1CCCC1>[CH3:9][O:10][C:11](=[O:46])[CH:12]=[CH:1][C:50]1[S:49][C:48]([CH3:47])=[N:52][C:51]=1[CH3:55]
Reactant: CC1=NC(C)(C=O)CS1
Reactant: COC(=O)C(NC(=O)c1c(C)cc(-n2nnnc2NCc2cccc3[nH]ccc23)cc1C)P(=O)(OC)OC
Reactant: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C=Cc1sc(C)nc1C
Temperature: -40 °C
Reaction time: 0.08 h

Procedure:
1,1,3,3-Tetramethylguanidine (53 μL, 0.42 mmol) is added to a solution of rac.-N-[2,6-dimethyl-4-[5-[(1H-indol-4-yl)methylamino]tetrazol-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 330; 108.3 mg, 0.2 mmol) in tetrahydrofuran (2 mL) at −40° C. The solution is stirred at −40° C. for 5 min and then 2,4-di-methylthiazole-4-carboxaldehyde (Example 43; 56.4 mg, 0.4 mmol) is added. The solution is stirred at −40° C. for 1 h and then allowed to stir at room temperature for 4 h. The solution is quenched with pH 6 phosphate buffer, diluted with ethyl acetate (15 mL) and the separated organic layer is washed with pH 6 phosphate buffer (10 mL) and brine (10 mL). The organic phase is dried (MgSO4), filtered, evaporated under reduced pressure. The residue is chromatographed over silica gel (increasing percentages of ethyl acetate in petroleum ether) and the appropriate fractions are combined and evaporated to yield to give (Z)-2-[2,6-dimethyl-4-[5-[(1H-indol-4-yl)methylamino]tetrazol-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid methyl ester.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])[CH2:2][CH3:3].C(=O)(O)[O-].[Na+].Cl[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CCOCC>[CH3:21][O:20][C:18](=[O:19])[CH2:17][NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:5]=1
Reactant: CCCc1cccc(N)c1
Reactant: COC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCCc1cccc(NCC(=O)OC)c1
Reaction time: 24 h

Procedure:
3-n-Propyl-aniline (20 g, 148 mmol), sodium bicarbonate (24.9 g, 296 mmol) and methyl chloroacetate (24.0 g, 221 mmol) were mixed under nitrogen and stirred at 80°-90° C. for 24 h. The cooled reaction was poured into ether (100 ml) and filtered. The filtrate was washed with water (100 ml), dilute hydrochloric acid (100 ml) and water (100 ml), then dried and concentrated in vacuo. The oily product (21.2 g) was distilled on the Kugelrohr collecting the fraction boiling at 160°/0.35 mmHg to give the title compound (Intermediate 32) as a colourless liquid which solidified into a pale yellow, low melting solid (16.1 g, 53%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]([OH:20])[CH3:19])[CH:5]=[C:6]([F:17])[C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.CO.FC1C=C([C:31]2(O)CC[O:33][CH2:32]2)C=C(F)C=1>>[F:17][C:6]1[CH:5]=[C:4]([C:18]2([OH:20])[CH2:31][CH2:32][O:33][CH2:19]2)[CH:3]=[C:2]([F:1])[C:7]=1[B:8]1[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:15])([CH3:16])[O:9]1
Reactant: CC(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: OC1(c2cc(F)cc(F)c2)CCOC1
Solvent: CO
Product: CC1(C)OB(c2c(F)cc(C3(O)CCOC3)cc2F)OC1(C)C

Procedure:
Following the procedure of Intermediate 106, replacing 1-(3,5-difluorophenyl)ethanol with 3-(3,5-difluorophenyl)tetrahydrofuran-3-ol methanol (Intermediate 142) provided the title compound.
Reaction SMILES: C(C1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#N.[OH-:9].[Na+:10].[CH2:11]([OH:13])[CH3:12]>O>[N:8]1[CH:7]=[CH:6][CH:5]=[N:4][C:12]=1[C:11]([O-:9])=[O:13].[Na+:10]
Reactant: CCO
Reactant: [OH-]
Reactant: N#Cc1ncccn1
Agent: [Na+]
Solvent: O
Product: O=C([O-])c1ncccn1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a slurry of 2-cyanopyrimidine (50 g) in water (100 ml) at 2° C. was added a solution of sodium hydroxide (50 wt %, 45.6 g) in water (30 ml) with an exotherm to 50° C. The mixture was stirred at 55° C. for 2 h, ethanol (500 ml) was added and the mixture concentrated in vacuo to an oil. Ethanol (250 ml) was added and the mixture concentrated to a paste. Ethanol (250 ml) was added and the mixture stirred at 15-20° C. for 30 min. The precipitate was collected by vacuum filtration, washed with ethanol (100 ml) and dried in a 75° C. vacuum oven to afford 67.57 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.C[Al](C)C.CCCCCC.[C:29]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46](OC)=[O:47])=[CH:42][CH:41]=2)=[C:36]([CH3:50])[CH:35]=1)(=[O:31])[CH3:30]>C1(C)C=CC=CC=1.ClCCl>[C:29]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([N:15]3[C:16]4[CH:17]=[C:18]5[C:5]6([CH2:8][O:9][C:10]5=[CH:11][C:12]=4[CH2:13][CH2:14]3)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)=[O:47])=[CH:42][CH:41]=2)=[C:36]([CH3:50])[CH:35]=1)(=[O:31])[CH3:30]
Reactant: COC(=O)c1ccc(-c2ccc(CNC(C)=O)cc2C)cc1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(=O)NCc1ccc(-c2ccc(C(=O)N3CCc4cc5c(cc43)C3(CCN(C)CC3)CO5)cc2)c(C)c1
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 47.7 %

Procedure:
A stirred solution of 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8, 85 mg, 0.35 mmole) in toluene (10 ml) at room temperature under argon was treated with 2M trimethylaluminium in hexane (0.74 ml, 1.5 mmole). The mixture was stirred for 0.75 h, then treated with a solution of methyl 4'-acetamidomethyl-2'-methylbiphenyl-4-carboxylate (D21, 120 mg, 0.40 mmole) in toluene (5 ml) and heated at 90° C. for 2 h. The solution was allowed to cool, then poured carefully into a stirred slurry of silica gel (10 g) in dichloromethane (30 ml) and stirring continued until the effervescence had ceased. The silica gel slurry was then packed into a chromatography column and eluted with 0-10% MeOH/CH2Cl2 to afford the title compound (85 mg, 48%). This was converted to the oxalate salt, which crystallised form acetone.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[CH:12](OCC)(OCC)OCC>C(O)C>[NH2:7][N:6]1[C:4](=[O:5])[C:3]2[C:2](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:1]=[CH:12]1
Reactant: CCOC(OCC)OCC
Reactant: NNC(=O)c1ccccc1N
Solvent: CCO
Product: Nn1cnc2ccccc2c1=O

Procedure:
A mixture of 2-aminobenzhydrazide (7.16 g, 47.4 mmol) and triethyl orthoformate (8.3 mL, 49.9 mmol) in ethanol is heated at reflux for 3.5 hours under a nitrogen atmosphere, cooled and filtered to obtain the title product as a white solid, 6.06 g (79%), mp 209°-210.5° C.
Reaction SMILES: C[O:2][C:3](OC)([OH:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][CH:7]=1>O1CCOCC1.[Pd]>[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:14])=[O:2])=[CH:7][CH:8]=1)=[O:13]
Reactant: COC(O)(C=Cc1ccc(C=O)cc1)OC
Agent: [Pd]
Solvent: C1COCCO1
Product: O=Cc1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
A solution of 16.7 g of 4-formylcinnamic acid dimethyl acetal in 200 ml of dioxane was hydrogenated in the presence of 1 g of 5% palladium-on-carbon at room temperature and atmospheric pressure. After about 61/2 hrs., the theoretical volume of hydrogen was consumed and the uptake ceased. The reaction mixture was filtered through Celite and the filter cake was washed with 300 ml of dioxane. The filtrate was concentrated to a final volume of 200 ml, 200 ml of 1 N hydrochloric acid was added, the solution was stirred at room temperature for 4 hrs. and then evaporated to dryness. The residue was dissolved in 700 ml of methylene chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to a final volume of 100 ml and the solution was allowed to stand at 0° for 16 hrs. The precipitate was collected, washed with 1:1 methylene chloride-petroleum ether and dried at 55° for 4 hrs. under vacuum to give 10.9 g (81%) of 4-formyldihydrocinnamic acid as colorless crystals, m.p. 134°-138°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([O:22]CC)=[O:21])[C:11]3[CH:16]=[N:15][N:14]([CH:17]([CH3:19])[CH3:18])[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=[O:21])[C:11]3[CH:16]=[N:15][N:14]([CH:17]([CH3:19])[CH3:18])[C:12]=3[N:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)nc2c1cnn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3ccc(Cl)cc3)nc21
Reaction time: 2 h

Procedure:
The title compound was prepared in the same manner as described for intermediate 58 using ethyl 6-(4-chlorophenyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (400 mg, 1.163 mmol), Ethanol (6 mL), THF (1 mL), and added sodium hydroxide (1.939 mL, 5.82 mmol) wherein the reaction time was 2 h. The final product was collected as 330 mg (90%). LCMS E-S (M+H)=315.8. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, J=6.8 Hz, 6 H), 5.26-5.47 (m, 1 H), 7.62 (d, J=8.6 Hz, 2 H), 8.20 (s, 1 H), 8.28 (d, J=8.6 Hz, 2 H), 8.38 (s, 1 H), 14.03 (s, 1 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:3][CH2:2]1
Reactant: OCCC1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
To an ice-cold solution of 2-(tetrahydro-2H-pyran-4-yl)ethanol (1.00 g) in pyridine (6.5 mL) was added p-toluenesulfonyl chloride (1.5 g), followed by stirring at the same temperature for 30 minutes, and at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and then diluted aqueous hydrochloric acid (20 mL) was added to the residue, followed by twice extractions with ethyl acetate (20 mL). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=80/20-50/50) to obtain p-toluenesulfonic acid 2-(tetrahydro-2H-pyran-4-yl)ethyl ester (450 mg).