Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(OC[S:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH:15]([CH3:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:10][CH:9]=1)=O>CO.CCN(CC)CC>[SH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14](=[O:22])[CH:15]([CH3:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:13]=1
Reactant: COC(=O)CC(C)C(=O)c1ccc(SCOC(=O)C(F)(F)F)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CC(C)C(=O)c1ccc(S)cc1
Yield: 97 %

Procedure:
To the neat trifluoroacetate from Step D of this Example (12.3 g) was added a mixture of 1:1 MeOH-NEt3 (600 ml) and the resulting reaction mixture was evaporated under vacuum. The procedure was repeated twice more. The residue was dissolved in CH2Cl2, washed with 1N HCl and brine and dried over Na2SO4. Evaporation of the solvent gave the title compound as an oil (7.8 g, 97%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27][NH:28][CH3:29])=[CH:17][CH:16]=3)[C:10](=[O:30])[C:9]=2[N:8]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:7]=1)=O)C.C([NH2:41])=O.CO[Na].O>CN(C=O)C.CO>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([N:8]2[C:9]3[C:10](=[O:30])[N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[CH2:27][NH:28][CH3:29])=[CH:17][CH:16]=4)[CH2:12][CH2:13][C:14]=3[C:6]([C:4]([NH2:41])=[O:3])=[N:7]2)=[CH:32][CH:33]=1
Reactant: NC=O
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(-c3ccccc3CNC)cc1)C2=O
Agent: CO[Na]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CNCc1ccccc1-c1ccc(N2CCc3c(C(N)=O)nn(-c4ccc(OC)cc4)c3C2=O)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 1-(4-methoxy-phenyl)-6-(2′-methylaminomethyl-biphenyl-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (57, 13.5 g, 26.4 mmol) in DMF (50 mL) was treated with formamide (8.32 g, 6.2 mL, 184.8 mmol, 7.0 equiv) at room temperature, and the resulting reaction mixture was cooled down to 0-5° C. before being treated dropwise with a solution of MeONa (8.6 g, 9.05 mL, 39.6 mmol, 1.5 equiv) in methanol at 0-5° C. The resulting reaction mixture was stirred at 0-5° C. for 30 min before being gradually warmed up to room temperature for an additional 3 h. When HPLC and TLC showed the reaction was complete, the reaction mixture was slowly poured into water (600 mL). The resulting mixture was then stirred at room temperature for 1 h to precipitate the desired product. The solids were collected by filtration, washed with water (2×100 mL) and methyl tert-butyl ether (2×100 mL), dried in vacuo at 40-45° C. for 12 h to afford crude desired 1-(4-methoxy-phenyl)-6-(2′-methylaminomethyl-biphenyl-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide (58, 10.55 g, 12.71 g theoretical, 83%). This crude solids were subsequently recrystallized in a mixture of ethanol and methanol to afford the pure product. For 58, CIMS m/z 482 (M++H, C28H27N5O3).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2(O)[C:14]3[CH:15]=[C:16]([Br:19])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][N:10]3[CH:20]=[CH:21][CH:22]=[C:9]23)[CH2:4][CH2:3]1.Cl.C(#N)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([Br:19])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][N:10]3[CH:20]=[CH:21][CH:22]=[C:9]23)[CH2:6][CH2:7]1
Reactant: CN1CCC(C2(O)c3cc(Br)ccc3C=Cn3cccc32)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CN1CCC(=C2c3cc(Br)ccc3C=Cn3cccc32)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.5 %

Procedure:
1-Methyl-4-(9-bromo-11-hydroxy-11H-pyrrolo[2,1-b][3]benzazepin-11-yl)piperidine (8.8 g) is dissolved in 500 ml of chloroform and the solution stirred in an ice bath while dry hydrogen chloride gas is bubbled in until the solution is acidic. The flask is then stoppered and the mixture stirred at room temperature for six hours following which the mixture is carefully basified with dilute aqueous sodium carbonate. The layers are separated, the aqueous extracted twice with chloroform and the combined chloroform washed with dilute sodium bicarbonate and with water. After drying over magnesium sulfate the chloroform is removed on a film evaporator to give a dark brown oil. Trituration with acetonitrile gives slightly impure 1-methyl-4-(9-bromo-11H-pyrrolo[2,1-b][3]benzazepin-11-ylidene)piperidine (5.4 g, 64%), m.p. 138°-142° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)[C:21]1[CH:26]=[N:25][C:24]([C:27]([F:29])([F:30])[F:28])=[N:23][CH:22]=1)=[O:6]
Reactant: NCC(c1cnc(C(F)(F)F)nc1)N1CCOCC1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)N1CCOCC1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][N:22]([CH3:40])[C:23]([C:25]2([CH3:39])[CH2:28][CH2:27][N:26]2[C:29](=[O:38])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33](I)[CH:32]=2)=[O:24])=[CH:19][CH:18]=1>O1CCOCC1.O>[Cl:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][N:22]([CH3:40])[C:23]([C:25]2([CH3:39])[CH2:28][CH2:27][N:26]2[C:29](=[O:38])[CH2:30][C:31]2[CH:32]=[C:33]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:34]=[CH:35][CH:36]=2)=[O:24])=[CH:19][CH:18]=1
Reactant: CN(Cc1ccc(Cl)cc1)C(=O)C1(C)CCN1C(=O)Cc1cccc(I)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(Cc1ccc(Cl)cc1)C(=O)C1(C)CCN1C(=O)Cc1cccc(-c2ccccc2)c1
Temperature: 90 °C

Procedure:
To a solution of phenyl boronic acid (1.5 eq.) in Dioxane/H2O (9/1) were added Na2CO3 (4 eq.) and 1-[2-(3-iodo-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-methyl-amide, compound 8 (1 eq.). The flask was evacuated and backfilled with argon. Then Pd(PPh3)4 was added and the reaction was heated at 90° C. until completion. The crude was partitioned between water and EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with Heptane/EtOAc: 100/0 to 20/80) to afford 1-(2-biphenyl-3-yl-acetyl)-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-methyl-amide.
Reaction SMILES: C(OC1C=CC(N2CCN(CCCC3CCCCC3)CC2)=CC=1Cl)C1C=CC=CC=1.[CH2:31]([N:33]([CH2:57][CH3:58])[C:34]([N:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:47]=[CH:46][C:45]([O:48]CC3C=CC=CC=3)=[C:44]([F:56])[CH:43]=2)[CH2:38][CH2:37]1)=[O:35])[CH3:32]>>[CH2:57]([N:33]([CH2:31][CH3:32])[C:34]([N:36]1[CH2:37][CH2:38][N:39]([C:42]2[CH:47]=[CH:46][C:45]([OH:48])=[C:44]([F:56])[CH:43]=2)[CH2:40][CH2:41]1)=[O:35])[CH3:58]
Reactant: CCN(CC)C(=O)N1CCN(c2ccc(OCc3ccccc3)c(F)c2)CC1
Agent: Clc1cc(N2CCN(CCCC3CCCCC3)CC2)ccc1OCc1ccccc1
Product: CCN(CC)C(=O)N1CCN(c2ccc(O)c(F)c2)CC1
Yield: 57.2 %

Procedure:
Production Example 30 was repeated except that 1-(4-benzyloxy-3-chlorophenyl)-4-(3-cyclohexylpropyl)piperazine was replaced with N,N-diethyl-4-(4-benzyloxy-3-fluorophenyl)-1-piperazinecarboxamide (365 mg). The resulting crude product was purified on TLC (developer, chloroform:methanol=12:1) to provide N,N-diethyl-4-(3-fluoro-4-hydroxyphenyl)-1-piperazinecarboxamide (160 mg).
Reaction SMILES: [CH2:1]([PH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:8]([CH:10]=[O:11])=[O:9]>C(O)(C)C>[CH2:1]([P:7]1[CH:8]([OH:9])[CH:10]([OH:11])[P:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]([OH:9])[CH:10]1[OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=CC=O
Reactant: CCCCCCP
Solvent: CC(C)O
Product: CCCCCCP1C(O)C(O)P(CCCCCC)C(O)C1O
Temperature: 60 °C
Yield: 98 %

Procedure:
In a suitable autoclave equipped as in Example 1, are added 200 parts of mono-n-hexylphosphine (93% purity) and 500 parts of isopropanol, as solvent. The mixture is heated to 60° C. and 240 parts of a 40% aqueous glyoxal solution are added. The reaction is allowed to proceed for one-hour and the solid product formed is filtered and dried to give 272 parts (98% yield) of 1,4-di-n-hexyl-2,3,5,6-tetrahydroxy-1,4-diphosphorinane, m.p. 140°-147° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]1.C(N(C(C)C)C(C)C)C>>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:27]3[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]3)=[CH:4][CH:5]=2)[C:12](=[O:26])[CH:13]=1
Reactant: O=c1cc(OCc2ccccc2F)ccn1CCc1ccc(CBr)cc1
Reactant: CC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ccccc4F)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[4-(2-Fluoro-benzyloxy)-2-oxo-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 9.1c from 80 mg (0.19 mmol) 1-[2-(4-bromomethyl-phenyl)ethyl]-4-(2-fluoro-benzyloxy)-1H-pyridin-2-one (example 9.1b), 41 mg (0.29 mmol) N-piperidin-4-yl-acetamide and 84 μL (0.48 mmol) N-ethyl-diisopropylamine as base.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:12]([O-])=O.[Na+].N>O.C(O)(=O)C.C(OCC)(=O)C>[N+:9]([C:8]1[CH:7]=[CH:6][CH:5]=[C:3]2[C:2]=1[CH:1]=[N:12][NH:4]2)([O-:11])=[O:10]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: O=N[O-]
Agent: N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc2[nH]ncc12
Reaction time: 72 h

Procedure:
A mixture of 2-methyl-3-nitro-aniline (5.00 g, 32.9 mmol) and a solution of sodium nitrite (2.27 g, 32.9 mmol) in water (7.5 mL) in glacial acetic acid (750 mL) was was stirred for 15 minutes and allowed to stand at room temperature for 3 days. The mixture was concentrated under reduced pressure leaving a pale yellow solid which was dissolved in ethyl acetate (250 mL) and filtered through a plug of silica gel, rinsing with ethyl acetate. The combined ethyl acetate was concentrated under reduced pressure to provide a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.65 (m, 1H), 8.10 (m, 1H), 8.16 (m, 1H), 8.54 (s, 1H), 13.9 (s, 1H); MS (DCI/NH3) m/z 164 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([CH3:8])=[N:5][CH:4]=1)[CH3:2].C([Li])CCC.[C:14](OCC)(=[O:16])[CH3:15]>C1COCC1>[CH2:1]([C:3]1[S:7][C:6]([CH2:8][C:14]([CH3:15])=[O:16])=[N:5][CH:4]=1)[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCc1cnc(C)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cnc(CC(C)=O)s1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
600 mg (4.72 mmol) of 5-ethyl-2-methyl-1,3-thiazole [M. Poite et al., Bull. Chem. Soc. Fr., 2078-2085 (1962)] are dissolved in 20 ml of abs. THF and, at −78° C., 2.08 ml (5.18 mmol) of n-butyllithium (2.5 M solution in hexane) are added dropwise. After stirring at −78° C. for two hours, 706 mg (8.02 mmol) of ethyl acetate are added as a solution in 10 ml of abs. THF. The mixture is stirred at −78° C. for 1 h and then warmed to room temperature. It is then hydrolyzed with sodium bicarbonate solution, and the mixture is extracted three times with diethyl ether. The combined organic phases are dried with magnesium sulfate, and the solvent is removed in a rotary evaporator. The crude product is purified by MPLC (Biotage 40M cartridge, eluent: isohexane/ethyl acetate 80:20). 50 mg (6% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:31])[C:18]([C:20]1[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]=1[CH2:29][CH3:30])=[O:19])=[CH:7]2.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[NH:34][N:33]=[N:32][N:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:31])[C:18]([C:20]1[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]=1[CH2:29][CH3:30])=[O:19])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2c(Br)c(OCC#N)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2c(Br)c(OCc3nnn[nH]3)ccc2c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 55 %

Procedure:
A mixture of 2-ethyl-benzofuran-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (0.25 g, 0.5237 mmol), prepared in the previous step, sodium azide (0.10 g, 1.57 mmol) and ammonium chloride (0.084 g, 1.57 mmol) in 12 mL DMF was stirred under nitrogen at 100° C. for 5 h. The reaction was diluted with water, made basic with 1N NaOH and extracted four times with ethyl acetate. The combined organic extracts were acidified with 1N HCl, the solvent removed under reduced pressure and the resulting residue diluted with water. The solid foam that formed was collected by filtration and dried under reduced pressure to give the title compound (0.15 g, 56%) as a tan foam, MS m/z: 520 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)(=O)C.[CH:27]([NH2:29])=[NH:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:28][CH:27]=[N:29][C:14]=2[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N=CN
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cncnc1C2

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and formamidine acetate. See also: Hajos, Gyorgy; Snatzke, Guenther Liebigs Annalen der Chemie 1989, (1), 31-3.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@H:19]1[CH2:25][CH2:24][S:23][C@H:22]2[CH2:26][CH2:27][CH2:28][C@@H:29]([C:30]([O:32][CH3:33])=[O:31])[N:21]2[C:20]1=[O:34]>>[CH2:1]([C@@H:14](/[CH:13]=[CH:12]/[C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:18][C@H:19]1[CH2:25][CH2:24][S:23][C@H:22]2[CH2:26][CH2:27][CH2:28][C@@H:29]([C:30]([O:32][CH3:33])=[O:31])[N:21]2[C:20]1=[O:34])=[O:11])[C:15]([NH:18][C@H:19]1[CH2:25][CH2:24][S:23][C@H:22]2[CH2:26][CH2:27][CH2:28][C@@H:29]([C:30]([O:32][CH3:33])=[O:31])[N:21]2[C:20]1=[O:34])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCC[C@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N21
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](/C=C/[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CCC[C@@H](C(=O)OC)N4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
Methyl (4S,7S,10aS)-4-(2R)-2-benzyl-6-(((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepin-4-yl)amino)-6-oxohexanoyl)amino)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure F using Intermediate 4 (15 mg, 0.061 mmol) and (4S,7S,10aS)-methyl 4-amino-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (34.9 mg, 0.135 mmol) to give a white solid (25 mg, 56% yield). Anal. Calcd. for C35H48N4O8S2 m/z 716.6. found: 717.6 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.62 (1H, d, J=6.8 Hz), 7.40 (1H, d, J=7.3 Hz), 7.29-7.22 (2H, m), 7.21-7.11 (3H, m), 5.37 (1H, t, J=4.6 Hz), 5.33 (1H, t, J=4.4 Hz), 5.18-5.07 (3H, m), 5.07-5.00 (1H, m), 3.73 (3H, s), 3.69 (3H, s), 3.29-3.19 (1H, m), 3.18-3.09 (1H, m), 2.93 (1H, ddd, J=14.4, 6.4, 2.7 Hz), 2.87-2.73 (3H, m), 2.56-2.48 (1H, m), 2.48-2.36 (2H, m), 2.36-2.26 (2H, m), 2.25-2.17 (1H, m), 2.09-1.93 (5H, m), 1.82-1.48 (12H, m).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)=[O:5].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:2][CH2:3][C:4]([C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=2)=[O:5])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(C(=O)CN)cc1
Agent: Cl
Product: CCOC(=O)c1ccc(C(=O)CNC(=O)c2ccc(Cl)cc2)cc1
Yield: 54 %

Procedure:
In the same manner as in Reference Example 6, ethyl 4-(2-amino-1-oxoethyl)benzoate hydrochloride and 4-chlorobenzoyl chloride were condensed to obtain ethyl 4-[2-(4-chlorobenzoylamino)-1-oxoethyl]benzoate. Yield: 54%. NMR (CDCl3) δ 1.41 (3H, t, J=7 Hz), 4.43 (2H, q, J=7 Hz), 4.99 (2H, d, J=4 Hz), 7.23 (1H, brs), 7.46 (2H, d, J=8.5 Hz), 7.84 (2H, d, J=8.5 Hz), 8.09 (2H, d, J=8.5 Hz), 8.21 (2H, d, J=8.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[Li]CCCC.[N:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:24]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)([OH:26])[CH3:25])=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccncc1
Reactant: Fc1ccc(-c2cncs2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccncc1)c1ncc(-c2ccc(F)cc2)s1
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
To a solution of 5-(4-fluorophenyl)thiazole (0.1 g, 0.558 mmol) in dry THF (8 mL) at −78° C., was slowly added n-1.6 M BuLi in hexanes (0.7 mL, 1.117 mmol), the reaction mixture was stirred for 30 minutes and 1-(pyridin-4-yl)ethanone (0.13 mL, 1.117 mmol) in THF (8 mL) was added. The reaction mixture was stirred for 2 hours at −78° C., the reaction mixture quenched with saturated NH4Cl solution (50 mL), extracted with EtOAc (2×50 mL), the organic layer washed with water (50 mL), dried over Na2SO4 and concentrated under reduced pressure to obtain crude product. The crude product was purified by preparative TLC (5% methanol in dichloromethane) to give 1-(5-(4-fluorophenyl)thiazol-2-yl)-1-(pyridin-4-yl)ethanol as off-white solid (35 mg, 22% yield) in 99.6% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.50 (br s, 1H), 8.03 (s, 1H), 7.66-7.63 (m, 2H), 7.53 (br s, 2H), 7.24 (t, 2H), 6.99 (s, 1H), 1.89 (s, 3H); LC-MS m/z calculated for [M+H]+ 301.07. found 301.4.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].Br[CH2:12][C:13]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:1]([N:3]([CH2:12][C:13]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2]
Reactant: CCNc1cccc(C)c1
Reactant: O=C(CBr)OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCN(CC(=O)OCC(F)(F)F)c1cccc(C)c1
Yield: 94.5 %

Procedure:
A mixture of 13.5 g (0.1 mole) N-ethyl-m-toluidine, 22.1 g (0.1 mole) trifluoroethyl bromoacetate and 7.0 g (0.051 mole) potassium carbonate in 100 ml of acetone was heated at reflux for two hours. Water (10 ml) was added and the mixture heated at reflux overnight. Solvent was removed on a rotary evaporator, ether added and the layers separated. The aqueous layer was extracted with ether. The combined ether solution was washed once with 50 ml of water and dried over sodium sulfate. Removal of ether gave 26.0 g brown oil which gave one spot by thin layer chromatography and was used as isolated (94%).
Reaction SMILES: O.[C-:2]#[N:3].[Na+].[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C1C=CC=CC=1>[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][C:2]#[N:3])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [C-]#N
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: N#CCc1ccc(OCc2ccccc2)cc1
Yield: 95.7 %

Procedure:
In a 100 ml four-necked flask, there were placed 3.2 g of water, 1.23 g (0.025 mole) of sodium cyanide and 0.16 g of triethylbenzylammonium chloride, and a solution prepared by dissolving 5.3 g (0.023 mole) of 4-benzyloxybenzyl chloride in 6 g of benzene was further added thereto under stirring. Then, the resultant mixture was heated at a temperature of 80° C. for 5 hours under stirring to permit a reaction. After completion of the reaction, the formed organic layer is washed with water and dried over anhydrous sodium sulfate, followed by distilling off benzene to obtain 4.83 g (0.022 mole) of 4-benzyloxyphenylacetonitrile.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:25][N:26]([CH3:36])[C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>O1CCOCC1.O>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]2=[CH:7][C:5]1[O:6][C:2]([C:30]2[CH:31]=[N:32][C:27]([N:26]([CH3:36])[CH3:25])=[CH:28][CH:29]=2)=[CH:3][CH:4]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(Br)o1
Reactant: CN(C)c1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)c1ccc(-c2ccc(C=C3C(=O)Nc4ccc(Cl)cc43)o2)cn1
Temperature: 120 °C

Procedure:
To 3-((5-bromofuran-2-yl)methylene)-5-chloroindolin-2-one (50 mg, 0.155 mmol) in dioxane/water (5% water) was added Cs2CO3 (152 mg, 0.466 mmol) and 6-(dimethylamino)pyridin-3-ylboronic acid (34 mg, 0.186 mmol). The mixture was degassed with nitrogen for 5 minutes then heated in microwave for 20 minutes at 120° C. The solution was diluted with water and the solid formed was isolated by filtration. The solid was purified by HPLC to yield 5-chloro-3-((5-(6-(dimethylamino)pyridin-3-yl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=366).
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[CH:8]1([C:14](Cl)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1(C)C=CC=CC=1>[CH:8]1([C:14]2[O:15][C:7]3[CH:6]=[CH:12][CH:13]=[CH:8][C:9]=3[CH:10]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: c1ccc2oc(C3CCCCC3)cc2c1
Yield: 147.6 %

Procedure:
A mixture of 13 g (0.0289 mole) of the above product, 8.77 g triethylamine and 4.66 g (0.0318 mole) cyclohexylcarbonyl chloride and 120 ml toluene was heated at reflux under nitrogen for six hours, cooled, filtered to remove insoluble matter and the filtrate concentrated in vacuo. The residual solid was flash chromatographed, eluting with hexane to obtain 4.7 g (81%) of white crystals, m.p. 32°-34° C. Mass spectrum (m/e): 200 (M+).