Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=O.[CH2:3]([N:10]1[CH2:15][C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:13]([C:23]([OH:25])=[O:24])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[H][H]>[OH-].[Na+].CC(OC)(C)C.CO>[CH2:3]([N:10]1[CH2:11][CH2:12][CH:13]([C:23]([OH:25])=[O:24])[CH:14]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C(O)C1=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)CC1
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: COC(C)(C)C
Product: O=C(O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Yield: 72.8 %

Procedure:
A 185-mL stainless steel autoclave was charged under argon in a glove box (O2 content<2 ppm) with the hydrochloride salt of 1-benzyl-5-(4-chloro-phenyl)-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid (7.00 g, 21.36 mmol), [Ru(OAc)2((R)-(6,6′-dimethoxybiphenyl-2,2′-diyl)bis(di-2-furylphosphine)] (81.30 mg, 0.11 mol), [Ru(OAc)2((S)-(6,6′-dimethoxybiphenyl-2,2′-diyl)bis(di-2-furylphosphine)] (81.30 mg, 0.11 mol), triethylamine (3.00 mL, 21.42 mmol) and methanol (120 mL). The hydrogenation was run for 20 h at 30° C. under 40 bar of hydrogen. After the pressure was released, the white suspension was evaporated to dryness to yield 9.58 g of the crude title compound. The crude product was dissolved in 1 M NaOH (45 mL). TBME (50 mL) was added, the aqueous layer was separated and diluted with water (250 mL). Under stirring 2 M HCl (20.5 mL) was added (pH value=6.0). The formed precipitate was filtered off and washed with water (50 mL). The filter cake was dissolved in methanol (100 mL) and the colorless solution evaporated to dryness to yield 5.13 g (70%) of the title compound. MS (m/e): 330.2 [(M+H)+].
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30]([C:39]5[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[C:41]([C:49]([F:52])([F:51])[F:50])[CH:40]=5)=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.CO>CO>[F:52][C:49]([F:50])([F:51])[C:41]1[CH:40]=[C:39]([C:30]2[N:21]3[CH:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH2:7])[CH2:11][CH2:10][CH2:9]5)=[CH:13][CH:14]=4)=[N:19][C:20]3=[N:32][C:31]=2[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:44]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:42]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(-c5ccccc5)c(-c5cc(C(F)(F)F)cc(C(F)(F)F)c5)n4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: CO
Product: NC1(c2ccc(-c3nc4nc(-c5ccccc5)c(-c5cc(C(F)(F)F)cc(C(F)(F)F)c5)n4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 5-6 (38 mg, 0.05 mmol) in 1 mL of MeOH was added 4M HCl/MeOH (2 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 5-7.
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5](Cl)=[O:6])[CH:3]=1.[C:13]1([Mg]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C1COCC1>[C:1]([C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5](=[O:6])[C:2]2[CH:10]=[CH:9][CH:8]=[CH:4][CH:3]=2)[CH:3]=1)(=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cccc(C(=O)c2ccccc2)c1
Yield: 75 %

Procedure:
According to the general mode of operation described above, 203 g (1 mole) of isophthaloyl dichloride in 500 ml of THF is reacted with 274 g (2 moles) of phenyl magnesium chloride. The subsequent hydrolysis is effected with the aid of a dilute hydrochloric acid solution. By cooling, the diketone crystalises. 1,3-dibenzoyl-benzene is obtained in a yield of 75%. The product is recrystallised from ethanol. White crystals are obtained, the melting point of which is 100° C., which corresponds to the formula: ##STR5##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](OC)=[O:18])[CH:12]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=1
Reactant: CCCc1cccc(C)c1-c1cccc(C(=O)OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cccc(C)c1-c1cccc(CO)c1
Temperature: 0 °C
Yield: 88.5 %

Procedure:
To a solution (6.3 mL) of methyl 2′-methyl-6′-propylbiphenyl-3-carboxylate (0.63 g, 2.35 mmol) in tetrahydrofuran was added lithium aluminum hydride (0.089 g, 2.35 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 2 hrs. Sodium sulfate 10 hydrate (1.5 g, 4.7 mmol) was gradually added to the reaction mixture, and the mixture was stirred at room temperature for 5 hrs. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-2/1) to give the title compound (0.50 g, yield 88%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C@@H:20]([C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH2:21][CH2:22][OH:23].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:31][O:30][C:27]1[N:26]=[CH:25][C:24]([C@H:20]([NH:19][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=4)[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:21][CH2:22][OH:23])=[CH:29][CH:28]=1
Reactant: COc1ccc([C@H](N)CCO)cn1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc([C@@H](CCO)Nc2ncnc3c2CN(c2ccc(C)cn2)CC3)cn1

Procedure:
A reaction mixture of 4-chloro-5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidine (45 mg, 0.17 mmol) and (R)-3-amino-3-(6-methoxypyridin-3-yl)propan-1-ol (31 mg, 0.17 mmol) (prepared similarly according to the method for Intermediate 10) in acetonitrile (2 mL) and N,N-diisopropylethylamine (60 μL, 0.34 mmol) was subjected to microwave irradiation at 180° C. for 1 h. The reaction mixture was concentrated and purified by semi-prep HPLC to give a light yellow foam.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][C:35]([N:37]2[CH2:42][CH2:41][CH2:40][C@@H:39]([C:43](=[O:58])[NH:44][C@H:45]([C:51]3[CH:52]=[N:53][CH:54]=[C:55]([OH:57])[CH:56]=3)[CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH2:38]2)=[O:36])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[F:59][C:60]1[CH:67]=[CH:66][C:65]([CH2:68]O)=[CH:64][C:61]=1[C:62]#[N:63].N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl.C1COCC1>[C:62]([C:61]1[CH:64]=[C:65]([CH:66]=[CH:67][C:60]=1[F:59])[CH2:68][O:57][C:55]1[CH:56]=[C:51]([C@@H:45]([NH:44][C:43]([C@@H:39]2[CH2:40][CH2:41][CH2:42][N:37]([C:35](=[O:36])[CH2:34][CH2:33][CH:30]3[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:26])[CH2:32][CH2:31]3)[CH2:38]2)=[O:58])[CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH:52]=[N:53][CH:54]=1)#[N:63]
Reactant: N#Cc1cc(CO)ccc1F
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCc2ccc(F)c(C#N)c2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 7.8 %

Procedure:
Polymer bound triphenylphosphine (30 mg) and tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(5-hydroxypyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 5e, 30 mg, 60 μmol) were stirred in dichloromethane for 30 minutes. 2-Fluoro-5-(hydroxymethyl)benzonitrile (26 mg, 0.17 mmol) in THF was added and the mixture was cooled to 0° C. Dipropan-2-yl diazene-1,2-dicarboxylate (20 μL, 0.11 mmol) was added, the mixture was stirred for 3 hours at room temperature and then stored for 16 hours at 5° C. After filtration the filtrate was concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography on silica gel (ethyl acetate 100%) to yield 3.2 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-1-{5-[(3-cyano-4-fluorobenzyl)oxy]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl.N1C=CC=CC=1>[C:8]1([CH2:14][C:15]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)Oc1ccccc1
Reaction time: 0.67 h
Yield: 95.6 %

Procedure:
Phenol (47.9 g) was dissolved in dichloromethane (250 ml) and pyridine (44.3 g). Phenylacetyl chloride (78.8 g) was added with stirring over 40 min., and the resulting mixture allowed to stand at room temperature for 1 hr. The mixture was washed sequentially with water, twice with dilute hydrochloric acid, once with dilute sodium hydroxide solution, and then once with saturated brine. The solution was dried and evaporated to give phenyl phenylacetate 103.3 g., m.pt 39°-41°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]2=O)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:8]2
Reactant: CCCCCCCCC1Cc2ccc(Br)cc2C1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCC1Cc2ccc(Br)cc2C1
Temperature: 0 °C
Yield: 91.8 %

Procedure:
Subsequently, 45.9 g (0.14M) of 6-bromo-2-n-octyl-1-indanone and 162.4 g (1.42M) of trifluoroacetic acid were placed in a 500 ml-reaction vessel. To the mixture, 41.4 g (3.57×10-1M) of triethylsilane was added dropwise in 15 minutes at room temperature. After the addition, the resultant mixture was heat-refluxed for 3.5 hours. After the reaction, the reaction mixture was poured into ice water and subjected to extraction with toluene, followed by successive washing with water and NaHCO3 aqueous solution, drying with anhydrous magnesium sulfate and distilling-off of the solvent. The resultant residue was subjected to vacuum distillation to obtain 40.3 g of 5-bromo-2-n-octylindan (Yield: 93.1%).
Reaction SMILES: [C:1](OCC)(=O)[CH2:2][C:3]([CH3:5])=O.[C:10]([CH2:12][C:13]([NH2:15])=O)#[N:11].[OH-]>>[C:10]([CH:12]1[C:3]([CH3:5])=[CH:2][CH2:1][NH:15][CH2:13]1)#[N:11]
Reactant: N#CCC(N)=O
Reactant: CCOC(=O)CC(C)=O
Agent: [OH-]
Product: CC1=CCNCC1C#N

Procedure:
reacting ethyl acetoacetate with cyanoacetamide and a hydroxide of an alkali metal, in the presence of an organic solvent, at a temperature of from 60° C. to 80° C., for 1 to 4 hours, to produce 3-cyano-2,6-dihydro-4-methylpyridine;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:9](=[O:10])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:11][CH:12]=2)[CH:3]=1
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 4-bromophthalic acid anhydride (100 g) in benzene (500 ml) was added aluminum chloride (118 g), and the mixture was stirred at room temperature for 1 hr. and subsequently refluxed for 30 min. After cooling the reaction mixture, it was diluted with ethyl acetate (200 ml) and poured into ice water. Conc. hydrochloric acid (50 ml) was added and the mixture was stirred at room temperature for 30 min. After separating the organic layer, the layer was washed successively with 4N hydrochloric acid, water and brine, dried over sodium sulfate and concentrated until crystals precipitated. The crude crystals were collected by filtration, and recrystallized from toluene/ethyl acetate (10:1) to give 4-bromo-2-benzoylbenzoic acid (59 g) as colorless crystals.
Reaction SMILES: [C:1]1([S:7][CH2:8]P(=O)(OCC)OCC)[CH:6]=[CH:5]C=C[CH:2]=1.C([Li])CCC.CN1CCN([C:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[C:33](=[O:40])[C:32]3[CH:41]=[CH:42][CH:43]=[CH:44][C:31]=3[CH:30]=2)CC1.Cl>C1COCC1.C(Cl)(Cl)Cl>[S:7]1[CH:8]=[CH:5][CH:6]=[C:1]1/[CH:2]=[C:29]1\[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33](=[O:40])[CH2:32][C:41]2[CH:42]=[CH:43][CH:44]=[CH:31][C:30]\1=2
Reactant: CN1CCN(c2cc3ccccc3c(=O)c3ccccc23)CC1
Reactant: CCOP(=O)(CSc1ccccc1)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C1Cc2ccccc2/C(=C/c2cccs2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 175.3 %

Procedure:
To a stirred solution of 3.25 g (12.5 mmol) of diethyl phenylthiomethylphosphonate in 7.0 mL of THF at 0° C. under N2 was added 7.8 mL of a 1.6M solution of n-butyllithium dropwise via syringe. The solution was stirred at 0° C. for 45 minutes, followed by the dropwise addition of a solution of 3.04 g (10.0 mmol) of 10-(4'-methylpiperazin-1-yl)-5H-dibenzo[a,d]cyclohepten-5-one in 10.0 mL of THF via cannula. After stirring for 1 hour at 0° C., the solution was warmed to 22° C. over 45 minutes, and stored at -5° C. for 48 hours. The reaction mixture was poured into 200 mL of 5% HCl and stirred rapidly with 300 mL of CHCl3 for 1 hour. The organic layer was worked up to give 5.3 g of a yellow foam which was chromatographed on 500 g of SiO2 using CHCl3 to give 2.14 g (65%) of product as a yellow foam. A small sample was crystallized from CH3OH to give a pale yellow solid. m.p. 203.5°-205° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1OC)([O-:3])=[O:2].[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19]>O>[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH:16][CH2:17][CH:18]([OH:20])[CH3:19])([O-:3])=[O:2]
Reactant: COc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]
Reactant: CC(O)CN
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(NCC(C)O)c([N+](=O)[O-])c1
Temperature: 60 °C

Procedure:
0.05 mol (10.6 g) of 2,6-dinitro-4-methylanisole is introduced gradually, whilst stirring, into 30 ml of 1-aminopropan-2-ol. The reaction medium is heated at 60° C. for 30 minutes and then poured into 120 g of iced water. The expected product precipitates. It is filtered off, washed with water and then recrystallised from an aqueous-alcoholic mixture. After drying in vacuo, it melts at 80° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:3]1.[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O.[BH4-].[Na+]>>[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:22][CH:23]=2)[CH2:3]1
Reactant: O=Cc1ccccc1F
Reactant: NC(=O)c1ccc(Oc2ccc(C3CCCNC3)cc2)nc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc(C3CCCN(Cc4ccccc4F)C3)cc2)nc1
Yield: 42.9 %

Procedure:
Using a method similar to Example 324, 6-(4-piperidin-3-yl-phenoxy)-nicotinamide (free base of compound of example 322) (0.0305 g, 0.103 mmol), 2-fluoro-benzaldehyde (0.0160 mL, 0.152 mmol), and sodium borohydride (0.0093 g, 0.246 mmol) provide 0.0179 g (43%) of the title compound as a white foam: high resolution mass spectrum (electrospray): m/z calc for C24H25FN3O2 406.1931, found 406.1936; 1H NMR (CDCl3): 8.56 (d, 1H, J=2.4 Hz), 8.14 (dd, 1H, J=2.4, 8.8 Hz), 7.37 (dt, 1H, J=1.9, 7.3 Hz), 7.27-7.18 (m, 3H), 7.09 (dt, 1H, J=1.0, 7.3 Hz), 7.06-6.97 (m, 3H), 6.93 (dd, 1H, J=1.0, 8.8 Hz), 5.71 (s br, 2H), 3.56 (s, 2H), 3.04-2.97 (m, 1H), 2.93 (d, 1H, J=10.7 Hz), 2.85 (tt, 1H, J=3.4, 11.2 Hz), 2.12-2.01 (m, 2H), 1.96-1.88 (m, 1H), 1.81-1.64 (m, 2H), 1.41 (dq, 1H, J=4.4, 11.7 Hz).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:9][C:10]1[C:11]([OH:20])=[C:12]([O:18][CH3:19])[CH:13]=[C:14]([CH:17]=1)[CH:15]=[O:16].C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)C.CCCCCC>CN(C=O)C>[I:9][C:10]1[CH:17]=[C:14]([CH:13]=[C:12]([O:18][CH3:19])[C:11]=1[O:20][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:15]=[O:16]
Reactant: ClCc1ccccc1
Reactant: COc1cc(C=O)cc(I)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)cc(I)c1OCc1ccccc1

Procedure:
Benzyl chloride (30 g, 0.24 mol) was added to a solution of 5-iodovanillin (60g, 0.216 mol) in DMF (250 mL) containing potassium carbonate (50 g). The mixture was stirred at 80° C. for 1.5 h or until TLC (hexane ethyl acetate; 4:1, v/v; Rf 0.5) showed the reaction to be complete. The mixture was then cooled and the solvent was decanted into ice water (1 L). The product was extracted with ethyl ether and the ethereal layer was washed with water, dried, and evaporated in vacuo to an oil, which solidified upon standing: mp 53°-54° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][NH:32][CH2:33][CH2:34][OH:35]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]([CH2:33][CH2:34][OH:35])[CH3:31])=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1
Reactant: CNCCO
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(CCO)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(2-hydroxy-ethyl)-methyl-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and 2-methylamino-ethanol following General Procedure B.
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH:8]2[NH:10][C:11]2[C:12]3[N:25]=[N:24][N:23]([CH:26]4[CH2:30][CH2:29][CH:28]([OH:31])[CH:27]4[OH:32])[C:13]=3[N:14]=[C:15]([S:17]([CH2:20]CC)(=O)=O)[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[S-].[Na+]>O1CCCC1.O>[C:1]1([CH:7]2[CH2:9][CH:8]2[NH:10][C:11]2[C:12]3[N:25]=[N:24][N:23]([CH:26]4[CH2:30][CH2:29][CH:28]([OH:31])[CH:27]4[OH:32])[C:13]=3[N:14]=[C:15]([S:17][CH3:20])[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCS(=O)(=O)c1nc(NC2CC2c2ccccc2)c2nnn(C3CCC(O)C3O)c2n1
Agent: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1nc(NC2CC2c2ccccc2)c2nnn(C3CCC(O)C3O)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of product from step b) (0.15 g) in tetrahydrofuran (10 ml) was treated with sodium methanethiolate (0.046 g) in water (1 ml). The solution was stirred at room temperature overnight. The solution was concentrated in vacuo and residue was purified by chromatography (SiO2, ethyl acetate:dichloromethane 1:1 as eluant) to afford the title compound (0.095 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7]Cl)[N:6]=1.[CH2:9]([CH2:11][NH2:12])[OH:10]>ClCCl>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][NH:12][CH2:11][CH2:9][OH:10])[N:6]=1
Reactant: NCCO
Reactant: Cc1nc(CCl)cs1
Solvent: ClCCl
Product: Cc1nc(CNCCO)cs1
Yield: 85 %

Procedure:
2-Methyl-4-(chloromethyl)thiazole (2.24 g) was treated with ethanolamine (11.6 mL, 10 equivalents) in dichloromethane at 25° C. for 16 hrs. The solvent was evaporated and the residue partitioned between ethyl acetate and brine. The organic layer was separated and extracted with ethyl acetate (5×). The organic layers were combined and washed with brine, dried over Na2SO4, and the solvents were evaporated to give 2.4 g (85%) of title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:11][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[C@@H:5]([C:12](=[O:14])[CH3:13])[C:4]([CH3:15])=[CH:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C([O-])(=O)C.[Na+]>[OH-].[Na+]>[C:16]([O:1][C@H:2]1[CH:3]=[C:4]([CH3:15])[C@H:5]([C:12](=[O:14])[CH3:13])[C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:11]1)(=[O:18])[CH3:17]
Reactant: CC(=O)[C@H]1C(C)=C[C@H](O)CC12CCCC2
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)O[C@H]1C=C(C)[C@H](C(C)=O)C2(CCCC2)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A mixture of 8:92 cis/trans-1-(9-hydroxy-7-methylspiro[4.5]dec-7-en-6-yl)ethanone (4.2 g, 20.2 mmol) was treated with acetic anhydride (4 ml, 42.3 mmol) and sodium acetate (1.65 g, 20.2 mmol). The resulting mixture was stirred at 80° C. for 1 h, poured into cold 2N aqueous NaOH (50 ml), and extracted twice with MTBE (40 ml). The combined organic phases were washed with water (40 ml), with a saturated aqueous solution of NaCl (40 ml), dried (MgSO4), and concentrated. FC (300 g SiO2, hexane/MTBE 8:1) of the crude product (4.82 g) gave 8:92 cis/trans-10-acetyl-9-methylspiro[4.5]dec-8-en-7-yl acetate (4.1 g, 82%).
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21].C(=O)(O)[O-].[Na+]>CN(C=O)C.CC(N(C)C)=O>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:9]2[C:4]3[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: O=c1[nH]cnc2cnc(F)cc12
Reactant: Nc1ccc(F)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Fc1cc2c(Nc3ccc(F)c(Br)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.7 %

Procedure:
A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (93) (4.0 g, 24.2 mmol), thionyl chloride (100 mL) and a catalytic amount of DMF (3 drops) was stirred under reflux for 1 h. The resulting solution was evaporated under reduced pressure at 45° C. (bath temperature) to give a light brown solid. To this solid was added a mixture of 3-bromo-4-fluoroaniline (5.1 g, 26.8 mmol) and dry DMA (25 mL). The reaction mixture was stirred at room temperature for 40 min, then a 5% solution of sodium bicarbonate (250 mL) was added and the mixture was stirred at room temperature for 15 min. The precipitated solid was collected by filtration and washed successively with water and hexane several times, before being dried under vacuum over silica gel to give N-(3-bromo-4-fluorophenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (162) (8.13 g, 99%), mp 275-277° C. (literature mp 269-270° C.; Smaill et al. J Med Chem, 1999, 42, 1803-1815); 1H NMR δ [(CD3)2SO] 10.12 (s, 1H), 8.97 (s, 1H), 8.74 (s, 1H), 8.32 (dd, J=6.4, 2.6 Hz, 1H), 8.23 (poorly resolved d, J=0.8 Hz, 1H), 7.93-7.87 (m, 1H), 7.46 (t, J=8.8 Hz, 1H). Anal. Calcd for C13H7BrF2N4: C, 46.32; H, 2.09; N, 16.62%. Found C, 46.54; H, 3.33; N, 16.42%.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]([N:9]1[CH:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:12][CH2:11][NH:10]1)=[O:8])=O)C>C(O)(=O)C>[O:3]=[C:4]1[N:10]2[CH2:11][CH2:12][CH2:13][CH:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[N:9]2[C:7](=[O:8])[CH2:6]1
Reactant: CCOC(=O)CC(=O)N1NCCCC1C(=O)OC(C)(C)C
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C1CCCN2C(=O)CC(=O)N12
Yield: 66 %

Procedure:
A solution of 16.9 g of tert.butyl 2-(2-ethoxycarbonylacetyl)hexahydropyridazine-3-carboxylate in 350ml of glacial acetic acid was heated at 100° C. for 1.5 hours. Evaporation gave an oil which was chromatographed on silica gel to yield 9.45 g (66%)of tert.butyl hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate in the form of a pale yellow solid having a melting point of 121°-122° C. (from chloroform/hexane).