Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([NH:17][CH:5]=[N:4][C:3]#[N:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Solvent: ClC(Cl)Cl
Product: N#CN=CNc1nc(OCc2ccc(F)cc2)ncc1F
Temperature: 90 °C
Yield: 183.2 %

Procedure:
Cyanamide (8.00 g, 190.0 mmol) was stirred at reflux in triethylorthoformate (60 mL) for 2 h. The reaction was cooled to room temperature and distilled to provide ethyl-N-cyanoimidate (12.5 g, bp=110-112° C./45 mm Hg).* To this imidate (1 mL) was added 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.05 g, 0.2 mmol) and the mixture was heated at 90° C. for 4 h, cooled, diluted with chloroform, filtered, and evaporated. The crude product was purified by reverse phase chromatography to furnish 0.053 g (17%) of the title compound as an off white solid: mp 148-149° C.; 1H NMR (300 MHz, CDCl3) δ 9.45 and 9.33 (bd, bs, J≈10 Hz, 1H), 8.33 and 8.25 (2d, J≈2 Hz, 1H), 7.46-7.38 (m, 2H), 7.11-7.01 (m, 2H), 5.35 and 5.33 (2s, 2H); HPLC-MS (ESI) m/z 290 (M+H)+, 288 (M−H)−. * Bridsen, Peter K., and Wang, Xiaodong, Synthesis, 1995, 855-8.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=1[CH3:16])=O.[NH2:17][C:18]([NH2:20])=[S:19].CCO>C1(C)C=CC=CC=1>[NH2:20][C:18]1[S:19][CH:2]=[C:3]([C:5]2[C:10]([CH3:11])=[CH:9][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=2[CH3:16])[N:17]=1
Reactant: CC(=O)Nc1cc(C)c(C(=O)CCl)c(C)c1
Reactant: NC(N)=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 86.2 %

Procedure:
A solution of compound N-(4-(2-chloroacetyl)-3,5-dimethylphenyl)acetamide (3.4 g, 14.2 mmol), thiourea (1.79 g, 23.6 mmol) and KI (150 mg) in toluene (50 mL) and 95% EtOH (50 mL) was refluxed overnight. After the solvent was distilled off, the residue was dissolved in EtOAc (600 mL) and washed with saturated Na2CO3 solution and brine successively, and dried over Na2SO4. After removal of solvent, the residue was subjected to column chromatography (silica gel, EtOAc:NH4OH=100:0.5) to furnish N-(4-(2-aminothiazol-4-yl)-3,5-dimethylphenyl)acetamide (3.2 g, 86.1% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([OH:19])=[O:18])[CH:13]=2)[CH:7]=1.Cl.CN(C)CCCN=C=NCC.O[CH2:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>O1CCCC1.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([O:19][CH2:48][CH2:49][CH2:50][N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[O:18])[CH:13]=2)[CH:7]=1
Reactant: OCCCN1CCOCC1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)OCCCN5CCOCC5)c[nH]4)c3)cc2F)c1
Temperature: 60 °C

Procedure:
To a stirred suspension of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (200 mg, 0.43 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 124 mg, 0.65 mmol) in 10 ml of anhydrous tetrahydrofuran were added N-(3-hydroxypropyl)morpholine (125 mg, 0.86 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol). The mixture was heated at 60° C. for 16 hours, cooled to room temperature and evaporated to dryness. The residue was purified by silica gel chromatography eluting with 3˜5% of methanol in chloroform to afford 3-morpholin-4-ylpropyl 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as white solid. Yield: 90 mg, 35%.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4][N:3]=1.Cl[CH2:17][C:18](=O)[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])O.[Na+]>C(O)C>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C:18]1[CH:1]=[C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[CH2:5][CH2:4][N:3]2[CH:17]=1
Reactant: COc1cc2c(cc1OC)C(C)=NCC2
Reactant: COC(=O)CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)Cc1cc2n(c1)CCc1cc(OC)c(OC)cc1-2
Yield: 56.4 %

Procedure:
10.3 g (50.0 mmol) of 1-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline, 8.3 g (55.0 mmol) of methyl 4-chloroacetoacetate and 12.6 g (150 mmol) of sodium hydrogen carbonate in 100 ml of ethanol are heated at reflux for 5 hours. After evaporation to dryness, the residue is taken up in 250 ml of dichloromethane and washed twice with 100 ml of water each time. After drying the organic phase over magnesium sulphate and then concentrating, the residue (15.5 g) is chromatographed on 500 g of silica (eluant: dichloromethane) to yield 8.5 g of the expected product (theory: 15.1 g).
Reaction SMILES: [C:1]([CH:3](P(OCC)(OCC)=O)[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH:41]=O>C1COCC1>[C:1]([C:3]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:8][CH2:9]1)=[CH:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=1)#[N:2]
Reactant: O=Cc1ccccn1
Reactant: CCOP(=O)(OCC)C(C#N)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(C#N)=Cc2ccccn2)CC1
Reaction time: 0.5 h

Procedure:
In a 100 ml 3 necked round bottom flask, intermediate tert-butyl 4-(cyano(diethoxyphosphoryl)methyl)piperazine-1-carboxylate (5.5 g) was taken in dry THF (25 ml) under nitrogen. Sodium bis trimethylsilyl amide (3.3 g) was added dropwise at 0° C. and stirred for 30 min, then pyridine-2-carboxaldehyde (1.67 g) in 15 ml dry THF was added dropwise to the above reaction mixture at 0° C. Reaction mixture was stirred at room temperature for overnight. TLC was checked no starting material and the reaction mixture was quenched with saturated ammonium chloride (50 ml) and ethyl acetate was added. The organic layer was washed with brine, dried and concentrated to get crude product compound tert-butyl 4-(1-cyano-2-(pyridin-2-yl)vinyl)piperazine-1-carboxylate as yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)C(=O)CC
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Product: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(=O)C(C)(C)C)cc1

Procedure:
The title compound was prepared by the method of Preparation 1c using (3-amino-4-chlorophenoxy)acetic acid methyl ester and 2-[4-(2,2-dimethylpropionyl)benzyl]-3-oxopentanoic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH:11]=[CH:10][C:9]=2[N+:23]([O-])=O)=[CH:4][CH:3]=1>[Pt].[I-].[Zn+2].[I-].C(OCC)(=O)C>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]2[C:9]([NH2:23])=[CH:10][CH:11]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(COc2ccc([N+](=O)[O-])c(NCc3ccc(Br)cc3)c2)nc1
Agent: [Pt]
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1ccc(COc2ccc(N)c(NCc3ccc(Br)cc3)c2)nc1
Reaction time: 18 h
Yield: 82.9 %

Procedure:
To a high pressure reactor were added N-(4-bromobenzyl)-5-((5-methylpyridin-2-yl)methoxy)-2-nitroaniline (78.4 g, 183 mmol), 5% Pt/C (35.7 g, 4.6 mmol), zinc iodide (5.84 g, 18.3 mmol) and ethyl acetate (1.5 L). The reactor was flushed with N2 and then stirred under an atmosphere of H2 (60 psi) for 18 h. The mixture was then filtered, washed with water (1 L), dried over magnesium sulfate and concentrated to dryness under reduced pressure to afford the title compound as an oil (60.4 g, 83%). MS (ESI): mass calcd. for C20H20BrN3O, 397.1; m/z found, 398.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.46-8.32 (m, 1H), 7.52-7.40 (m, 3H), 7.34 (d, J=8.0, 1H), 7.25-7.19 (m, 2H), 6.64 (d, J=8.1, 1H), 6.30-6.21 (m, 2H), 5.06 (s, 2H), 4.24 (s, 2H), 2.75 (bs, 2H), 2.32 (s, 3H).
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[F:47][C:48]1[CH:49]=[CH:50][C:51]([C:57]2[N:62]=[CH:61][CH:60]=[CH:59][N:58]=2)=[C:52]([CH:56]=1)[C:53](O)=[O:54]>>[F:47][C:48]1[CH:49]=[CH:50][C:51]([C:57]2[N:58]=[CH:59][CH:60]=[CH:61][N:62]=2)=[C:52]([CH:56]=1)[C:53]([NH:44][C@H:40]1[CH2:41][CH2:42][CH2:43][C@@H:39]1[NH:38][C:35]1[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=1)=[O:54]
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(F)ccc1-c1ncccn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 75 mg, 0.27 mmol) and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid (CAS number 1293284-57-7; 69 mg, 0.32 mmol) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:10][C:11]([F:24])([F:23])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][C:21]#[N:22]>>[F:10][C:11]([F:23])([F:24])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]1[C:21]([NH2:22])=[N:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: Nc1ccccc1C=O
Reactant: N#CCCc1ccccc1OC(F)(F)F
Product: Nc1nc2ccccc2cc1Cc1ccccc1OC(F)(F)F

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-aminobenzaldehyde and 3-(2-trifluoromethoxyphenyl)propionitrile.
Reaction SMILES: [CH:1]1([C:4](=[O:20])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([F:19])([F:18])([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1.[CH2:21]([O:23][CH:24](OCC)OCC)[CH3:22]>C(OC(=O)C)(=O)C>[CH:1]1([C:4](=[O:20])[C:5](=[CH:24][O:23][CH2:21][CH3:22])[C:6]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([F:15])([F:16])([F:17])([F:18])[F:19])=[CH:12][CH:13]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(OCC)OCC
Reactant: O=C(CC(=O)C1CC1)c1ccc(S(F)(F)(F)(F)F)cc1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(S(F)(F)(F)(F)F)cc1)C(=O)C1CC1
Yield: 103.5 %

Procedure:
A mixture of 3-cyclopropyl-1-(4-pentafluorosulphanylphenyl)-propan-1,3 -dione (0.82 g) and triethylorthoformate (3.1 g) in acetic anhydride (40 ml) was heated at reflux temperature for 6 hours. The excess reagent and solvent were evaporated to give 3-cyclopropyl-2-ethoxymethylene-1-(4-pentafluorosulphanylphenyl)-propan-1,3 -dione (1.0 g) as an orange oil. This was used directly in the subsequent reaction stage.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH3:40])[C:10]([O:12][C@@H:13]1[CH2:29][C@@H:28]2[C@@:16]([CH3:39])([C@@H:17]3[C@@H:25]([CH2:26][CH2:27]2)[C@:24]2(O)[C@@:20]([CH3:38])([C@@H:21]([C:31]4[CH:32]=[CH:33][C:34](=[O:37])[O:35][CH:36]=4)[CH2:22][CH2:23]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:11])=O)(C)(C)C.Cl>CCOC(C)=O>[NH2:8][C@H:9]([CH3:40])[C:10]([O:12][C@@H:13]1[CH2:29][C@@H:28]2[C@@:16]([CH3:39])([C@@H:17]3[C@@H:25]([CH2:26][CH2:27]2)[C:24]2[C@@:20]([CH3:38])([C@@H:21]([C:31]4[CH:32]=[CH:33][C:34](=[O:37])[O:35][CH:36]=4)[CH2:22][CH:23]=2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:11]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccc(=O)oc4)CC[C@]32O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](N)C(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@H]3C4=CC[C@H](c5ccc(=O)oc5)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
To a solution of (R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-((tert-butoxycarbonyl)amino)propanoate (23 mg, 0.041 mmol, 1 eq) in EtOAc (3 mL) was added HCl (4 M in EtOAc, 3 mL) in drops at 0° C. The resulting mixture was warmed to room temperature after 30 min and stirred for 2 h. The mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc (20 mL×3). The organic layer was washed with H2O (10 mL×4) and then dried over anhydrous Na2SO4, concentrated under reduced pressure. The crude product was then purified via Prep-TLC(CH2Cl2:MeOH=10:1) to afford the (R)-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-aminopropanoate (8 mg, 44.1% yield) as a white solid. LCMS (M+H+) m/z 440.6.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([O:7][C:8]2[CH:9]=[C:10]([NH2:23])[CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[S:36](Cl)(=[O:38])=[O:37].N1C=CC=CC=1>ClCCl.CN(C1C=CN=CC=1)C>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][C:12]2[CH:11]=[C:10]([NH:23][S:36]([C:27]3[CH:28]=[CH:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:26]=3)(=[O:38])=[O:37])[CH:9]=[C:8]([O:7][C:6]3[CH:24]=[CH:25][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:13]=2)=[CH:16][CH:17]=1)#[N:22]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: N#Cc1ccc(Oc2cc(N)cc(Oc3ccc(C#N)cc3)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(Oc2cc(NS(=O)(=O)c3ccc4ccccc4c3)cc(Oc3ccc(C#N)cc3)c2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
[3,5-Bis-(4-cyano-phenoxy)-phenyl]-amine (0.35 g, 1.07 mmol) and 2-naphthyl-sulphonyl chloride (0.29 g, 1.28 mmol) were dissolved in 10 ml of dichloromethane and cooled to 0° C. Further 0.18 ml (2.14 mmol) of pyridine and 15 mg (0.107 mmol) of DMAP was added to the reaction mixture and allowed to stirred overnight at RT. After completion, reaction mixture was diluted with 50 ml of dichloromethane and washed with 50 ml 1N HCl solution and then with brine. Organic layer was dried over anhydrous sodium sulphate and concentrated under vacuo. Thus obtained crude product was subjected to column chromatography and eluted with ethylacetate and hexane mixture to afford 0.4 g of the required product. Percentage purity (LCMS): 90.4% M+1=517.1+1.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29]C)/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH2:20][CH3:21])[C:12](=[O:22])[N:11]([CH2:23][CH2:24][CH3:25])[C:10]=2[N:9]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[OH:29])/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH2:20][CH3:21])[C:12](=[O:22])[N:11]([CH2:23][CH2:24][CH3:25])[C:10]=2[N:9]=1
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3ccc(OC)c(OC)c3)n2C)n(CCC)c1=O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccc(O)c(O)c3)n2C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
Compound 1 (770 mg, 1.87 mmol) obtained in Reference Example 1 was dissolved in 15 ml of methylene chloride. To the solution was added 5.6 ml (5.6 mmol) of boron tribromide (1.0M methylene chloride solution) under ice cooling in argon atmosphere, and the mixture was stirred overnight at room temperature. Methanol was added thereto and the mixture was separated with chloroform-an aqueous solution of sodium bicarbonate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography to give 550 mg (yield 77%) of Compound 53 as a yellow solid, which was then triturated with ether to give a yellow powder.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25]1[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH:30]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH:25]1[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(OCc4ccccc4)cc23)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(c2c[nH]c3ccc(OCc4ccccc4)cc23)CC1
Yield: 93.6 %

Procedure:
By a method similar to Preparation 20, using trifluoroacetic acid (1.6 mL), 5-benzyloxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (222 mg, 0.7 mmol), methylene chloride (3 mL) and triethylsilane (111 μL, 0.7 mmol) gave the tile compound as a yellow foam (210 mg) which was crystallized from ethyl acetate to give 160 mg of pale yellow crystals: mp=163-164° C.; MS(m/e): 321 (M+1), 379 (M+59); Calculated for C21H24N2O: Calcd: C, 78.72; H, 7.55; N, 8.74. Found: C, 78.63; H, 7.64; N, 8.78.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5](O)=[O:6].Cl.C[N:14](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CCN(CC)CC>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([NH2:14])=[O:6]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(O)cc(O)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1cc(O)cc(O)c1

Procedure:
After reaction step (a), the resulting amine (1 equiv.), 3,5-dihydroxybenzoic acid (1 equiv.), EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (1.2 equiv.), HOBt (1-hydroxybenzotriazole hydrate) (1.2 equiv.), and Et3N (4 equiv.) in CH2Cl2.DMF (9:1) were stirred for 12 hours at room temperature. Then the reaction mixture was diluted with EtOAc and the organic layer washed with brine. The combined organic layer was dried over anhydrous Na2SO4 and concentrated. Purification of the resulting crude product by flash silica gel chromatography provided corresponding 3,5-dihydroxybenzamide derivative. The above derivative (1 equiv.) and active carbonate 4 (1.1 equiv.) in THF were stirred under hydrogen atmosphere in presence of Pd—C (10%) for 12 hours at room temperature. Then the reaction mixture was filtered and the organic layer washed with brine. The combined organic layer was dried over anhydrous Na2SO4 and concentrated. Purification of the resulting crude product by flash silica gel chromatography provided compound 134 as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[OH-].[K+].[Br-].[Li+]>C1(C)C=CC=CC=1.O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:20][CH2:19]1
Reactant: OCc1ccc(O)cc1
Reactant: COc1ccccc1N1CCNCC1
Agent: [Br-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(Cc2ccc(O)cc2)CC1
Temperature: 25 °C
Yield: 56 %

Procedure:
4-Hydroxyphenyl methanol (124 g, 1 mole) and 192 g (1 mole) of 1-(2-methoxyphenyl)piperazine, together with 56 g (1 mole) of potassium hydroxide and 8.7 g (0.1 mole) of lithium bromide and 32.2 g (0.1 mole) of Aliquat 366 were dissolved in a mixture of 1 liter of toluene and 1 liter of water. The reaction mixture was refluxed for 24 hours, and then allowed to cool to room temperature. The organic layer was decanted and extracted twice with 500 ml of a 10% sodium hydroxide solution. The basic aqueous liquor was treated with ammonium acetate to provoke precipitation of the desired product. After filtration and drying under vacuum overnight at 50° C., 167 g (0.56 mole, 56% yield) of the title product was obtained as small white leaflets melting at 172° C.
Reaction SMILES: N[C:2](N)=[O:3].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][C:24]=2[NH2:33])[CH2:15][CH2:14]1>>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][N:21]2[C:22](=[O:34])[C:23]3[C:24](=[CH:25][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:27][CH:28]=3)[NH:33][C:2]2=[O:3])[CH2:17][CH2:18]1
Reactant: NC(N)=O
Reactant: COc1ccccc1N1CCN(CCNC(=O)c2ccc(NC(C)=O)cc2N)CC1
Product: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3cc(NC(C)=O)ccc3c2=O)CC1
Yield: 60 %

Procedure:
Four hundred and forty miligrams of urea was added to 1.5 g of 1-(2-methoxyphenyl)-4-[2-(4-acetylamino-2-aminobenzoyl)aminoethyl]piperazine to react at 160° C. for 8 hours. The reaction liquid was extracted with chloroform and purified through the silica gel chromatography to obtain 0.96 g of the titled compound (yield: 60%).
Reaction SMILES: [IH:1].Cl[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH2:16][CH3:17])[CH:12]=[CH:11][C:10]=2[F:18])[CH:6]=[C:5]([CH3:19])[N:4]=1>C(Cl)Cl>[CH2:16]([O:15][C:13]1[CH:12]=[CH:11][C:10]([F:18])=[C:9]([C:7]2[CH:6]=[C:5]([CH3:19])[N:4]=[C:3]([I:1])[N:8]=2)[CH:14]=1)[CH3:17]
Reactant: I
Reactant: CCOc1ccc(F)c(-c2cc(C)nc(Cl)n2)c1
Solvent: ClCCl
Product: CCOc1ccc(F)c(-c2cc(C)nc(I)n2)c1
Reaction time: 18 h
Yield: 57.4 %

Procedure:
Hydroiodic acid (57% in water, 8 mL, 106.39 mmol) was added portionwise to 2-chloro-4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidine (which may be prepared as described in Description 16) (2.18 g, 8.17 mmol) in DCM (30 mL) at 20° C. and the dark mixture was stirred for 18 hrs. The mixture was filtered and washed with a little DCM. The yellow solid was suspended in water/DCM and quenched by the addition of satd. aq. K2CO3 (care: gas evolved). After basification, satd. aq. sodium metabisulphite was added and stirring was continued for 5 mins. The mixture was diluted with further DCM and the phases were separated. The organic layer was dried (Na2SO4) and the solvent evaporated to afford 4-(5-ethoxy-2-fluoro-phenyl)-2-iodo-6-methyl-pyrimidine (D17) (1.68 g, 4.6908 mmol, 57.4% yield) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:36]2[CH:37]=[CH:38][C:39]([Cl:51])=[C:40]3[C:44]=2[N:43]([CH3:45])[N:42]=[C:41]3[NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[C:5]([C@@H:8]([NH:18][C:19](=[O:35])[CH2:20][N:21]2[C:25]3[C:26]([F:31])([F:30])[C@@H:27]4[CH2:29][C@@H:28]4[C:24]=3[C:23]([CH:32]([F:34])[F:33])=[N:22]2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][CH:7]=1.NC1C=C(C2C=CC([Cl:92])=C3C=2N(C)N=C3NS(C)(=O)=O)C([C@@H](NC(=O)OC(C)(C)C)CC2C=C(F)C=C(F)C=2)=NC=1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:36]2[CH:37]=[CH:38][C:39]([Cl:51])=[C:40]3[C:44]=2[N:43]([CH3:45])[N:42]=[C:41]3[NH:46][S:47]([CH3:50])(=[O:48])=[O:49])[C:5]([C@@H:8]([NH:18][C:19](=[O:35])[CH2:20][N:21]2[C:25]3[C:26]([F:31])([F:30])[C@@H:27]4[CH2:29][C@@H:28]4[C:24]=3[C:23]([CH:32]([F:34])[F:33])=[N:22]2)[CH2:9][C:10]2[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=2)=[N:6][C:7]=1[Cl:92]
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)cnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)c21
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)cnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)c(Cl)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21

Procedure:
Compound 53B was prepared according to the method presented for the synthesis of compound 49C in Example 49 substituting 53A for 49A to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ 7.17-6.94 (m, 2H), 6.87-6.54 (m, 2H), 6.53-6.19 (m, 3H), 4.96 (s, 1H), 4.72 (dd, 2H), 3.41 (s, 2H), 3.24 (d, 3H), 3.16-2.88 (m, 3H), 1.38 (dt, 1H), 1.13-0.99 (m, 1H). MS (m/z) 787 [M+H]+.