Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:9][CH2:8][CH2:7][C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)(=[O:22])=[O:21]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
3.7 g (25 mmole) p-cyanophenethylalcohol was dissolved in 15 ml dichloromethane, 5.2 ml (87.5 mmole) triethylamine was added and the mixture was cooled on an ice bath. 2.52 ml (32.5 mmole) methanesulfonyl chloride in 5 ml dichloromethane was slowly added at 0-7° C. The reaction was allowed to reach room temperature and then stirred at room temperature. The reaction mixture was washed with cooled 2 N hydrochloric acid, water, dried (sodium sulfate), filtered and the solvent was evaporated in vacuo to give 5.3 g (yield 95%) of 4-cyanophenethyl methanesulfonate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Br-:10].[Br-:11].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:10][C:6]1[CH:5]=[C:4]2[C:9](=[C:8]([Br:11])[CH:7]=1)[NH:1][CH2:2][CH2:3]2
Reactant: [Br-]
Reactant: c1ccc2c(c1)CCN2
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1cc(Br)c2c(c1)CCN2
Yield: 84.1 %

Procedure:
Part A: Indoline (2.2 g, 18.04 mmol), dissolved in dichloromethane (160 mL) was stirred with pyridinium tribromide (12 g, 37.6 mmol) for 16 h at 25° C. The reaction was quenched with sat NaHSO3 (50 mL) and water (50 mL). The dichloromethane was separated, dried (MgSO4) and stripped in vacuo. The residue was chromatographed on silica gel using 20% ethyl acetate/hexanes as eluent to give 5,7-dibromoindoline (4.2 g, 84% yield). 1H NMR(CDCl3) δ 7.28 (m, 1H), 7.11 (s, 1H), 3.96 (s br, 1H), 3.63 (t J=9 Hz, 1H), 3.13 (t J=9 Hz, 2H).
Reaction SMILES: C[O:2][C:3](=O)[N:4]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[C:5]1[CH:10]=[N:9][C:8]([CH3:11])=[C:7]2[O:12]C(C)(C)[O:14][CH2:15][C:6]=12.C(O)=O>C(O)C>[OH:12][C:7]1[C:6]2[CH2:15][O:14][C:3](=[O:2])[N:4]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[C:5]=2[CH:10]=[N:9][C:8]=1[CH3:11]
Reactant: COC(=O)N(Cc1ccc(C#N)cc1)c1cnc(C)c2c1COC(C)(C)O2
Solvent: CCO
Solvent: O=CO
Product: Cc1ncc2c(c1O)COC(=O)N2Cc1ccc(C#N)cc1
Yield: 68.2 %

Procedure:
The hydrolysis of (4-cyano-benzyl)-(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)-carbamic acid methyl ester (81) (5.1 g, 13.9 mmol) and subsequent cyclization was achieved by heating 81 in a 1:1 mixture of aqueous formic acid (20%) and ethyl alcohol at 80° C. for 2 hours. The evaporation of solvent, followed by the addition of water precipitated the product 4-(5-hydroxy-6-methyl-2-oxo-4H-pyrido[3,4-d][1,3]oxazin-1-ylmethyl)-benzonitrile (82) (2.8 g, 74% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([F:11])([F:10])[F:9])=[N:4][NH:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23](=[O:26])CBr)([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[C:18]([O:22][C:23]([N:5]1[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:8]([F:9])([F:11])[F:10])=[N:4]1)=[O:26])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1[nH]nc(C(F)(F)F)c1Cl
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(Cl)c(C(F)(F)F)nn1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 95 %

Procedure:
To 2.70 mmol of 4-chloro-5-methyl-3-trifluoromethylpyrazole and 3.9 mmol of potassium carbonate in 0.5M solution of acetonitrile add 3.25 mmol of t-butylbromoacetate. The reaction was allowed to stir at room temperature for an hour and then heated at 70° C. for 12 hours. The reaction was filtered, the filtrate concentrated to a crude oil. Fresh ether was added and the mixture was allowed to cool. The white crystals obtained were filtered and vaccum dried to give the desired intermediate 4-chloro-5-methyl-3-trifluoromethylpyrazole-1-carboxylic acid tertbutyl ester in 95% yield. LC-MS in FP m/z=300 (M++1)
Reaction SMILES: Br[CH:2]1[C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[S:4][CH2:3]1.Cl.[NH:14]1[CH:18]=[C:17]([CH2:19][C:20]([NH2:22])=[S:21])[N:16]=[CH:15]1>>[NH:14]1[CH:18]=[C:17]([CH2:19][C:20]2[S:21][C:2]3[CH2:3][S:4][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=4[C:11]=3[N:22]=2)[N:16]=[CH:15]1
Reactant: NC(=S)Cc1c[nH]cn1
Reactant: O=C1c2ccccc2SCC1Br
Agent: Cl
Product: c1ccc2c(c1)SCc1sc(Cc3c[nH]cn3)nc1-2

Procedure:
Starting compounds: 3-bromothiochroman-4-one, 4-imidazolyl thioacetamide hydrochloride
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH:7]([C:13](=O)[CH3:14])[C:8](OCC)=[O:9])=[C:4]([O:18][CH3:19])[CH:3]=1.C(=O)(O)O.[NH2:24][C:25]([NH2:27])=[NH:26]>CCO>[NH2:27][C:25]1[N:26]=[C:8]([OH:9])[C:7]([CH2:6][C:5]2[CH:16]=[CH:17][C:2]([OH:1])=[CH:3][C:4]=2[O:18][CH3:19])=[C:13]([CH3:14])[N:24]=1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1OC)C(C)=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCO
Product: COc1cc(O)ccc1Cc1c(C)nc(N)nc1O

Procedure:
A mixture of the product from step (ii) (23.35 g) and guanidine carbonate (15.9 g) in EtOH (300 ml) was heated under reflux for 24 h. The mixture was cooled and the solid filtered and washed with EtOH, water, EtOH then diethyl ether and dried to afford the subtitle compound, 11.36 g.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7](F)[CH:6]=1>O.CN(C)C=O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([S:2][CH3:1])[CH:6]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(Br)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A solution of sodium methanethiolate (2.25 g, 70.1 mmol) in water (50 mL) was added dropwise to a solution of 4-bromo-2-fluoro-1-nitrobenzene (6.42 g, 29.2 mmol) in N,N-dimethylformamide (150 mL) at 0° C. and the mixture was stirred for 1 hour. The mixture was filtered and the solid washed with water (3×150 mL) to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:30]([F:31])=[CH:29][C:5]2[N:6]([C:19](=[O:28])[CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[NH:12][N:13]=3)[C:4]=2[CH:3]=1.[Na].[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41]Cl)[CH2:36][CH2:35]1>CN(C)C=O.C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:30]([F:31])=[CH:29][C:5]2[N:6]([C:19](=[O:28])[CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[N:12]([CH2:41][CH2:40][N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)[N:13]=3)[C:4]=2[CH:3]=1
Reactant: CCCN(CCC)CC(=O)N1c2cc(F)c(F)cc2-n2c(n[nH]c2=O)-c2cccnc21
Reactant: CN1CCN(CCCl)CC1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: CCCN(CCC)CC(=O)N1c2cc(F)c(F)cc2-n2c(nn(CCN3CCN(C)CC3)c2=O)-c2cccnc21
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 6,7-difluoro-2,9-dihydro-9-[ (dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one in dimethylforamide is added a solution of sodium hydrided in mineral oil. The mixture is allowed to react at about 95°C. for 40 minutes and after cooling [2-(4-methylpiperazino)-ethyl]chloride in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 6,7-difluoro-2.9-dihydro-2-[2-(4-methylpiperazino)ethyl]-9-[(dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]-benzodiazepin-3-one.
Reaction SMILES: [C@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][C@@H:3]([NH2:7])[CH2:2]1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1.CS(O)(=O)=O>CN1CCCC1=O.C(#N)C>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([NH:7][C@H:3]3[CH2:4][CH2:5][CH2:6][C@@H:1]([NH:8][C:10]4[C:19]5[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=5)[N:13]=[CH:12][CH:11]=4)[CH2:2]3)=[CH:11][CH:12]=[N:13]2)=[CH:18][CH:17]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: N[C@@H]1CCC[C@H](N)C1
Agent: CS(=O)(=O)O
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: Clc1ccc2c(N[C@@H]3CCC[C@H](Nc4ccnc5cc(Cl)ccc45)C3)ccnc2c1
Yield: 21.9 %

Procedure:
23.2 g of cis-cyclohexane-1,3-diamine and 80.5 g of 4,7-dichloroquinoline are reacted at 150° C. in 400 ml of N-methyl-2-pyrrolidone under argon for 24 hours. After cooling insoluble material is filtered off and the filtrate is treated with 600 ml of water. The separated crude product is introduced into 400 ml of water and 100 ml of glacial acetic acid. The mixture is extracted three times with 200 ml of ethyl acetate each time and then adjusted to pH 12 by the addition of 600 ml of 2N NaOH. The separated crystalline diamine is recrystallized from 270 ml of dimethylformamide, 20.1 g of pure product being obtained. This is converted into the dimethanesulphonate in 200 ml of boiling acetonitrile with 6.4 ml of methanesulphonic acid. 19.5 g of colourless crystalline salt, m.p.:>250° C., are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[S:28]([C:32]1[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=1)(=[O:31])(=[O:30])[NH2:29]>>[S:28]([C:32]1[CH:33]=[C:34]([NH:38][C:25]([C:24]2[CH:23]=[N:22][N:15]3[C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:9])[F:10])=[C:2]([CH3:1])[CH:3]=4)=[N:13][C:14]=23)=[O:26])[CH:35]=[CH:36][CH:37]=1)(=[O:30])(=[O:31])[NH2:29]
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(N)(=O)=O)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 542.1 [(M−H)−]; mp 245° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[O:21]=[C:22]1[C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][N:23]1[CH2:39][C:40](O)=[O:41].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]2[CH2:10][CH2:11][N:12]([C:40](=[O:41])[CH2:39][N:23]3[CH2:24][CH2:25][C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:22]3=[O:21])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Fc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(c2ccccc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-((4-fluorophenyl)(phenyl)methyl)piperazine (0.27 g, 1.00 mmol) in dichloromethane (20 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.61 mg, 0.005 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.40-7.49 (m, 4H), 7.25-7.35 (m, 10H), 7.17-7.24 (m, 3H), 7.08-7.17 (m, 2H), 4.36 (s, 1H), 4.14-4.15 (br s, 2H), 3.40-3.48 (m, 4H), 3.35 (t, J=6.6 Hz, 2H), 2.71 (t, J=6.5 Hz, 2H), 2.22-2.28 (m, 4H).
Reaction SMILES: C([Li])(CC)C.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH3:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].CON(C)[C:26](=[O:30])[CH2:27][CH2:28][CH3:29]>C1CCCCC1.C1COCC1>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH2:22][C:26](=[O:30])[CH2:27][CH2:28][CH3:29])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C
Reactant: CCCC(=O)N(C)OC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCCC(=O)Cc1c(NC(=O)OC(C)(C)C)cccc1OC
Temperature: -60 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A solution of 50 mL (65 mmol) of 1.3M sec-butyl lithium in cyclohexane was added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (7.7 g, 32.5 mmol) in 100 mL of THF keeping the temperature below -40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to -10° C. and then the bath replaced. After the temperature had cooled to -60° C., 4.3 g (32.5 mmol) of N-methoxy-N-methylbutanamide in an equal volume of THF was added dropwise. The reaction mixture was stirred 1 hour, the cooling bath removed and stirred an additional 22 hours. It was then poured into a mixture of 200 mL of ether and 200 mL of 0.5N HCl. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated at reduced pressure to give 9.9 g of crude 1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-pentanone. This material was dissolved in 100 mL of methylene chloride and 20 mL of trifluoroacetic acid and stirred for a total of 23 hours. The mixture was washed with water, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 2.19 g of 4-methoxy-2-propyl-1H-indole as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[H-].[Na+].[CH2:22]([O:29][C:30]1[C:35]([CH2:36]Cl)=[C:34]([CH3:38])[CH:33]=[C:32]([CH3:39])[N:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[CH2:22]([O:29][C:30]1[C:35]([CH2:36][N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([Cl:1])[C:3]([O:13][CH:14]([CH3:19])[C:15]([F:18])([F:16])[F:17])=[CH:4][CH:5]=3)[C:10]2=[O:12])=[C:34]([CH3:38])[CH:33]=[C:32]([CH3:39])[N:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Reactant: CC(Oc1ccc2c(c1Cl)C(=O)NCC2)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(CN2CCc3ccc(OC(C)C(F)(F)F)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
To a solution of 8-chloro-7-[(1,1,1-trifluoropropan-2-yl)oxy]-3,4-dihydroisoquinolin-1(2H)-one (58a, 50 mg, 0.17 mmol) in dry DMF (6 mL) was added portionwise NaH (60% in oil, 21 mg, 0.51 mmol) at 0° C. under N2 atmosphere. The resulting mixture was stirred at 0° C. for 10 minutes and then 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 76 mg, 0.29 mmol) was added. The resulting mixture was stirred at room temperature overnight. To the reaction mixture was added H2O (20 mL). The mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (4×15 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc=6:1) to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-[(1,1,1-trifluoropropan-2-yl)oxy]-3,4-dihydroisoquinolin-1(2H)-one (58b, 70 mg, 80%) as a colorless oil.
Reaction SMILES: ClCl.[C:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=1)(=[O:5])[CH3:4].C(Cl)[Cl:26]>C(O)C>[Cl:26][CH2:4][C:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=1)=[O:5]
Reactant: ClCCl
Reactant: CC(=O)c1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Agent: ClCl
Solvent: CCO
Product: O=C(CCl)c1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
Chlorine gas was led into a stirred mixture of 6-acetyl-4-(3-chloro-4-fluoroanilino)quinazoline (0.11 g), methylene chloride (40 ml) and ethanol (60 ml) and the mixture was cooled to a temperature in the range 20 to 25° C. After 10 minutes the supply of chlorine was stopped and the reaction mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated to give 6-(2chloroacetyl)-4-(3-chloro-4-fluoroanilino)quinazoline (0.114 g) which was used without further purification.
Reaction SMILES: C([NH:3][CH:4](/[CH:11]=[C:12](/[CH2:21][P:22]([O:28]C(C)C)([O:24]C(C)C)=[O:23])\[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.C[Si](C)(C)Br.C(O)C>ClCCl>[NH2:3][CH:4](/[CH:11]=[C:12](/[CH2:21][P:22]([OH:28])([OH:24])=[O:23])\[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CCC/C(=C\C(CC(=O)OCC)NC=O)CP(=O)(OC(C)C)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCC/C(=C\C(N)CC(=O)OCC)CP(=O)(O)O
Reaction time: 20 h

Procedure:
4.3 g (9.9 mmol) of diethyl E-2-formylamino-4-diisopropylphosphonomethyl-hept-3-ene-1,7-dicarboxylate are dissolved in 14 ml of dichloromethane and 5.2 ml (40 mmol) of trimethylbromosilane are added dropwise at room temperature to the solution. The reaction mixture is allowed to stand for 20 hours and, after addition of 14 ml of ethanol, allowed to stand for a further 19 hours. The reaction mixture is concentrated on a rotary evaporator and the residue is taken up in 14 ml of ethanol. After addition of 14 ml of propylene oxide and 14 ml of ethanol, the resultant suspension is stirred for 90 minutes and then filtered with suction, affording diethyl E-2-amino-4-phosphonomethyl-hept-3-ene-1,7 -dicarboxylate of m.p. 218°-220° C. (decomp.).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][CH:11]1[CH2:18][CH2:17][CH:16]2[CH2:19][CH:12]1[CH2:13][CH2:14][C:15]2=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:21])[NH:10][CH:11]1[CH2:18][CH2:17][CH:16]2[CH2:19][CH:12]1[CH2:13][CH2:14][CH:15]2[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCC2CC1CCC2=O)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1CCC2CC1CCC2O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
780 mg of (6-Oxo-bicyclo[3.3.1]non-2-yl)-carbamic acid benzyl ester (100) were dissolved in 14 mL of THF under argon, cooled to 0° C. and 113 mg of sodium borohydride were added. The mixture was stirred for 2 h at 0° C., water was added and the pH of solution was adjusted to 2 by addition of 2M HCl. The aqueous layer was extracted with ethyl acetate three times. The combined organic layer was dried over sodium sulfate and evaporated to dryness to give 0.72 g of the desired product. Rt=1.23 min (Method C). Detected mass: 290.3 (M+H+).
Reaction SMILES: [CH:1]([N-:4]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[C:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:18]=[C:17]2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])=[CH:12][CH:11]=1.C1(C)C=CC(S(C#N)(=O)=O)=CC=1.C(OCC)C>C1COCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:20]([C:1]#[N:4])=[C:19]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[N:18]=[C:17]2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])=[CH:12][CH:11]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1C#N
Reaction time: 1 h

Procedure:
Lithium diisopropyl amide (LDA) (5.25 mL of a 2 M solution in THF, 0.0105 mol) is added dropwise to a cooled solution (−70° C.) of tert-butyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (4.24 gram, 0.010 mol) in anhydrous THF (80 mL) in a nitrogen atmosphere and the resulting mixture is stirred for one hour. A solution of p-toluenesulfonyl cyanide (1.88 gram, 0.011 mol) in anhydrous THF (20 mL) is added dropwise and the resulting red solution is stirred for one hour at −70° C. and then allowed to attain room temperature. Diethyl ether is added and the resulting solution is quenched with water and filtered over hyflo. The organic layer is collected and washed with water, dried over MgSO4, filtered and concentrated in vacuo to give an oil. This oil is purified by column chromatography (dichloromethane, silicagel) to give 3.4 gram of tert-butyl 1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate. Recrystallisation from diisopropyl ether gave crystalline tert-butyl 1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (2.57 gram, 57% yield). Melting point: 210–212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]CC2C=CC=CC=2)=[CH:15][CH:14]=1.CO.[H][H]>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1ccc(Oc2ccc(OCc3ccccc3)cc2)c(Cl)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Yield: 94 %

Procedure:
4-Benzyloxyphenyl 2-chloro-4-trifluoromethylphenyl ether (25 g., 0.066 mole), purified by recrystallization from methanol, ethyl acetate (200 ml.) and 10% palladium on charcoal (1.0 g.) are charged to a 2-liter Paar hydrogenation bottle and shaken in a hydrogen atmosphere (40-45 psi) until hydrogen uptake ceases. The catalyst is then removed by filtration and the solvent and toluene are removed in vacuo to give 17.9 g. (94% yield) of 4-(2-chloro-4-trifluoromethylphenoxy)phenol, mp 55°-6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:9]=2[O:24][CH3:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:33][C:34]1[C:35]([OH:45])=[C:36]([S:41](Cl)(=[O:43])=[O:42])[CH:37]=[C:38]([Cl:40])[CH:39]=1>C(Cl)Cl>[Cl:33][C:34]1[C:35]([OH:45])=[C:36]([S:41]([N:15]([CH2:14][C:10]2[C:9]([O:24][CH3:25])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)(=[O:43])=[O:42])[CH:37]=[C:38]([Cl:40])[CH:39]=1
Reactant: COc1c(CNCc2ccc(F)cc2)cccc1-c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cccc1-c1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 40.9 %

Procedure:
A solution of 1-(4′-chloro-2-methoxybiphenyl-3-yl)-N-(4-fluorobenzyl)methanamine (590 mg, 1.684 mmol, 1.0 eq) in dry DCM under nitrogen at 0° C. and treated slowly with triethylamine (492 mg, 4.8 mmol, 3 eq). The reaction mixture was stirred for 10 minutes and treated with a solution of 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (527 mg, 2.018 mmol, 1.2 eq) dissolved in DCM. The resulting mixture was stirred for 12 h at ambient temperature and concentrated under reduced pressure. The residue was further diluted with water and extracted with ethyl acetate. The organic layer was dried under anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (60-120) eluting with 15-20% ethyl acetate/hexane to afford the title compound (0.400 g, 50%). 1H NMR (400 MHz, DMSO-d6) δ 3.32 (s, 3H), 4.52-4.53 (d, 4H), 7.04-7.08 (m, 3H), 7.17-7.24 (m, 4H), 7.43-7.52 (m, 5H), 7.77 (s, 1H). MS (ESI): 577.8 (M−H)−.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O>>[F:14][C:15]([F:24])([F:25])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3ccccc3C(F)(F)F)CC2)nc[nH]1

Procedure:
6-[4-(2-Trifluoromethyl-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-(trifluoromethyl)benzaldehyde. Mass spectrum (ES) MH+=339.