Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:26][CH2:25][C:8]2([C:12](=[O:13])[N:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[C:27]1(=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:32][C:27]1([CH2:1][S:2]([N:5]2[CH2:6][CH2:7][C:8]3([C:12](=[O:13])[N:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=4)[CH2:10][CH2:9]3)[CH2:25][CH2:26]2)(=[O:4])=[O:3])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C1CCCC1
Reactant: CS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)CC1(O)CCCC1)CC2

Procedure:
The title compound was prepared in analogy to example 208 step B from 8-methanesulfonyl-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 208, step A) and cyclopentanone. White solid. MS (ESI): 477.2 (MH+).
Reaction SMILES: [ClH:1].[OH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[C:5]([O:20][CH2:21][CH:22]2[CH2:24][S:23]2)[CH:4]=1>C(OCC)(=O)C>[Cl:1][CH2:24][CH:22]([SH:23])[CH2:21][O:20][C:5]1[CH:4]=[C:3]([OH:2])[C:16]2[C:15](=[O:17])[C:14]3[C:9]([O:8][C:7]=2[CH:6]=1)=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][CH:13]=3
Reactant: COc1cccc2c(=O)c3c(O)cc(OCC4CS4)cc3oc12
Reactant: Cl
Solvent: CCOC(C)=O
Product: COc1cccc2c(=O)c3c(O)cc(OCC(S)CCl)cc3oc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
Aqueous ethyl acetate 1M-HCl (3 mL) was added to 1-hydroxy-5-methoxy-3-(thiiran-2-ylmethoxy)-9H-xanthen-9-one (30 mg, 0.09 mmol) prepared in Example 3, followed by stirring at room temperature for 3 hours, and the reaction solvent was removed under reduced pressure. Ether was added to the residue, followed by sonication, and the solvent was removed to give the title compound (30 mg, 90.1%) as a light brown solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[CH2:19][NH:18][N:17]([S:22]([CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)(=[O:24])=[O:23])[C:16]=3[CH2:15]2)[CH2:11][O:10][C@@H:9]1[C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[C@@H:9]1[C@@H:8]([NH2:7])[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[CH2:19][NH:18][N:17]([S:22]([CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)(=[O:23])=[O:24])[C:16]=3[CH2:15]2)[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2CC3=C(C2)N(S(=O)(=O)C2CCCC2)NC3)CO[C@@H]1c1cc(F)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1C[C@@H](N2CC3=C(C2)N(S(=O)(=O)C2CCCC2)NC3)CO[C@@H]1c1cc(F)ccc1F
Reaction time: 1.5 h

Procedure:
A solution of the intermediate obtained in Step A above (49 mg, 0.089 mmol) in dichloromethane (4 mL) was treated with trifluoroacetic acid (2 mL) at room temperature. After 1.5 h, the reaction mixture was concentrated and purified by preparative thin layer chromatography eluting with 5% methanol containing 10% NH4OH in dichloromethane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@@H:6]([CH3:13])[N:5]([CH:14]3[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]3)[C:4]=2[N:3]=1.C(N(CC)CC)C.[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)#[N:30]>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:35]3[CH:36]=[C:31]([CH:32]=[CH:33][CH:34]=3)[C:29]#[N:30])[C:7](=[O:12])[C@@H:6]([CH3:13])[N:5]([CH:14]3[CH2:15][CH2:16][C:17]([F:21])([F:20])[CH2:18][CH2:19]3)[C:4]=2[N:3]=1
Reactant: C[C@@H]1C(=O)Nc2cnc(Cl)nc2N1C1CCC(F)(F)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1C(=O)N(c2cccc(C#N)c2)c2cnc(Cl)nc2N1C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51 %

Procedure:
To a stirred solution of (7R)-2-chloro-8-(4,4-difluorocyclohexyl)-7-methyl-7,8-dihydropteridin-6(5H)-one (1.80 g, 5.7 mmol) in dichloromethane (75 mL) was added triethylamine (8.07 ml, 57.8 mmol), cupric acetate (2.09 g, 11.56 mmol) and (3-cyanophenyl)boronic acid (1.69 g, 11.56 mmol) followed by 4 Å molecular sieves (2 g). The reaction mixture was stirred for 48 h at rt with an air balloon on the top. The reaction mixture was then filtered over celite to give a clear solution. The solution was washed with aqueous saturated sodium bicarbonate (50 mL×2), dried over anhydrous sodium sulfate and evaporated to give a crude material, which was then purified by silica gel column chromatography (eluent: 2% methanol in dichloromethane) to give the desired product (51%). 1HNMR (300 MHz, CDCl3): δ 1.50 (d, J=6.9 Hz, 3H), 1.80-2.24 (m, 8H), 4.40-4.61 (m, 2H), 7.20-7.26 (m, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.55 (s, 1H), 7.69 (t, J=7.8 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14]4([O:20][CH2:19][CH2:18][O:17]4)[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][CH:3]=1.[CH3:21][C:22]([S:25]([NH2:27])=[O:26])([CH3:24])[CH3:23].CCOC(C)=O>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14]4([O:20][CH2:19][CH2:18][O:17]4)[CH2:13][CH2:12]3)[C:8]2=[N:27][S:25]([C:22]([CH3:24])([CH3:23])[CH3:21])=[O:26])=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1c2cc(Br)ccc2CC12CCC1(CC2)OCCO1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCC1(CC2)OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
6″-Bromodispiro[1,3-dioxolane-2,1′-cyclohexane-4′,2″-inden]-1″(3″H)-one (Intermediate 71, 320 mg, 0.95 mmol), 2-methylpropane-2-sulfinamide (173 mg, 1.42 mmol) and titanium ethoxide (0.391 mL, 1.90 mmol) were dissolved in 2-Me THF (5 mL) and heated to reflux overnight. The reaction was stopped and was left to cool down to r.t. EtOAc and water were added under stirring. The mixture was left to stand still for 2 h. The organic phase was collected by filtration, dried using a phase separator and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of 0-30% EtOAc in heptane to give the title compound (290 mg, 69% yield): 1H NMR (500 MHz, CDCl3) δ ppm 1.35 (s, 9H) 1.48-1.54 (m, 1H) 1.61 (dd, 1H) 1.67-1.77 (m, 2H) 1.81-1.90 (m, 2H) 2.10 (br. s., 2H) 2.95-3.05 (m, 2H) 3.95-4.02 (m, 4H) 7.25 (s, 1H) 7.60 (dd, 1H) 8.62 (br. s., 1H); MS (ES+) m/z 440.0 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([CH3:17])[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[C:5]([N+:18]([O-])=O)[CH:4]=1.[H][H]>[Ni].CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([NH2:18])[C:6]([NH:9][CH:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:17])=[CH:7][CH:8]=1
Reactant: CC(Nc1ccc(Cl)cc1[N+](=O)[O-])c1cccnc1
Reactant: [H][H]
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: CC(Nc1ccc(Cl)cc1N)c1cccnc1
Yield: 100 %

Procedure:
A mixture of 46 parts of N-(4-chloro-2-nitrophenyl)-α-methyl-3-pyridinemethanamine monohydrochloride and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 41.5 parts (100%) of 4-chloro-N1 -[1-(3-pyridinyl)ethyl]-1,2-benzenediamine monohydrochloride as a residue.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[CH:18]=[CH:19]/[C:20](O)=[O:21]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:20](=[O:21])/[CH:19]=[CH:18]/[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)[CH2:4]2
Reactant: O=C(O)/C=C/c1ccccn1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1ccccn1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(2-pyridyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 258 (MH+).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:25]/[C:26](/[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:27]\[CH2:28][CH2:29][CH:30]=O>ClCCl>[Br:2][C:1]([Br:5])=[CH:30][CH2:29][CH2:28]/[CH:27]=[C:26](\[CH3:25])/[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCC/C(C)=C/CCC=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCC/C(C)=C/CCC=C(Br)Br
Temperature: 0 °C
Yield: 77.7 %

Procedure:
A dichloromethane solution (100 ml) of CBr4 (85 g, 256 mmols) was added dropwise to a stirred and ice-cooled dichloromethane solution (300 ml) of Ph3P (138 g, 526 mmols). To the mixture, a dichloromethane solution (100 ml) of the (E)-5-methyl-4-tetradecenal (5) (29.0 g, 129 mmols) was added while being cooled at 0° C. and stirred, followed by stirring the mixture for 15 minutes at 0° C. The reaction of this mixture was terminated by ice-cooled water (100 ml), and after 20 minutes of stirring, the organic layer was separated. The organic solution was dried (magnesium sulfate), and then concentrated in a vacuum. The residue was triturated with pentane (1 L), and insoluble Ph3PO was removed by filtration. The filtrate was concentrated in a vacuum, and then the oily residue was subjected to silica gel column chromatography, and eluted with n-hexane to obtain 38.1 g (77.6%) of oily (E)-1,1-dibromo-6-methyl-1,5-pentadecadiene (6).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:6][CH:5]=[C:4]([CH2:17][CH3:18])[N:3]=1.[CH2:19]([NH2:21])[CH3:20].Cl.[OH-].[Na+]>>[Cl:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[C:8]([C:7]1[C:2]([NH:21][CH2:19][CH3:20])=[N:3][C:4]([CH2:17][CH3:18])=[CH:5][CH:6]=1)=[O:16]
Reactant: CCc1ccc(C(=O)c2cccc(Cl)c2)c(Cl)n1
Reactant: CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCNc1nc(CC)ccc1C(=O)c1cccc(Cl)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
A mixture of 2-chloro-3-(3-chlorobenzoyl)-6-ethylpyridine (3.4 g, 12 mmol) and 70% ethylamine aqueous solution (15 ml) was sealed in a tube and stirred at 100° C. for 4 hours. The reaction solution was cooled to room temperature and then transferred into a separating funnel. This was acidified by adding 1 N hydrochloric acid, vigorously shaken and then alkalified by adding 1 N sodium hydroxide aqueous solution. This was extracted with chloroform, the resulting organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and then the filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3-(3-chlorobenzoyl)-6-ethyl-2-ethylaminopyridine (2.6 g, 76%) as a yellow oily material.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:7]([CH3:14])[CH:6]=[C:5]([CH3:15])[C:3]=1[NH2:4].C[Al](C)C.[NH2:20][C:21]1[CH:25]=[CH:24][S:23][C:22]=1[C:26](OC)=[O:27].Cl>ClCCCl>[NH2:20][C:21]1[CH:25]=[CH:24][S:23][C:22]=1[C:26]([NH:4][C:3]1[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:2]=1[CH3:1])=[O:27]
Reactant: Cc1cc(C)c(N2CCCC2)c(C)c1N
Reactant: COC(=O)c1sccc1N
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCCl
Product: Cc1cc(C)c(N2CCCC2)c(C)c1NC(=O)c1sccc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
To a solution of 2,4,6-trimethyl-3-pyrrolidin-1-yl-aniline, (1.5 g, 7.6 mmol) in anhydrous 1,2 dichloroethane (20 mL), chilled to 0° C. under N2, was added a solution of trimethylaluminum (2M in hexanes) (7.6 mL, 15.2 mmol). Upon completion of the addition, the ice bath was removed and the reaction was stirred for 30 min. at room temperature. Methyl 3-amino-2-thiophenecarboxylate (0.95 g, 0.8 equivalents.) was added in one portion to the flask, and the reaction mixture was refluxed for 18 hours. The reaction mixture was acidified with hydrochloric acid (2N) (2×50 mL) and washed with dichloromethane (2×50 mL). The combined aqueous layers were then adjusted basic using a saturated, aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2×50 mL). The combined organic ethyl acetate extracts were dried with magnesium sulfate, filtered, and concentrated under reduced pressure to yield a brown oil. The material was further purified by silica gel chromatography using 5% ethyl acetate in hexanes as the mobile phase (gradient) to yield 3-amino-N-(2,4,6-trimethyl-3-pyrrolidin-1-ylphenyl)thiophene-2-carboxamide as a yellow foam (640 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]([CH3:24])([CH3:23])[C:15]=3[CH:14]=[C:13]([C:25](=[O:27])[CH3:26])[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)([OH:30])=[O:29].[OH-].[K+]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]3[C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]([CH3:24])([CH3:23])[C:15]=3[CH:14]=[C:13]([C:25](=[O:27])/[CH:26]=[CH:35]/[C:34]3[CH:37]=[CH:38][C:31]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)[CH:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1cc(-c2ccc(C(C)(C)C)cc2)c2c(c1)C(C)(C)CCC2(C)C
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(-c2cc(C(=O)/C=C/c3ccc(C(=O)O)cc3)cc3c2C(C)(C)CCC3(C)C)cc1
Yield: 61 %

Procedure:
In a manner similar to that of Example 2b, by reacting 710 mg (2.0 mmol) of 1-[4-(4-tert-butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]ethanone with 260 mg (1.8 mmol) of 4-carboxybenzaldehyde and 1.0 mL (8 mmol) of 47% KOH. The desired product is obtained in the form of white crystals (m=590 mg; yield=61%; m.p.=241° C.).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1.[NH2:31][CH2:32][CH2:33][OH:34].CO>O1CCCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[S:22][CH:23]=[C:19]([CH2:18][S:17][C:4]3[C:5]([C:15]#[N:16])=[C:6]([C:10]4[CH:14]=[CH:13][NH:12][N:11]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:31][CH2:32][CH2:33][OH:34])[N:3]=3)[N:20]=2)=[CH:25][CH:26]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cc[nH]n1
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1c(NCCO)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cc[nH]n1
Reaction time: 0.5 h

Procedure:
58 mg (0.124 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(1H-pyrazol-3-yl)pyridine-3,5-dicarbonitrile were dissolved in 1 ml of tetrahydrofuran, and 15 mg (0.247 mmol) of 2-aminoethanol were added. After 30 minutes of stirring, methanol was added, the mixture was filtered and the filtrate was purified by preparative HPLC. This gave 63 mg (100% of theory) of the target compound.
Reaction SMILES: C1(C2C=CC([CH:8]=[O:9])=CC=2)CC1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:22][CH3:23])([CH3:21])[CH3:20])=[C:15]([Cl:24])[CH:14]=1.[Li]CCCC.CCCCCC.CN(C=O)C>>[Cl:24][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[C:19]([O:22][CH3:23])([CH3:21])[CH3:20])[CH:8]=[O:9]
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: COC(C)(C)c1ccc(Br)cc1Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(C)(C)c1ccc(C=O)cc1Cl
Yield: 62 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 310 mg of 4-bromo-2-chloro-1-(1-methoxy-1-methyl-ethyl)-benzene (1.18 mmol), 1.1 ml of a 1.6 molar solution of n-BuLi in hexane (1.76 mmol) and 457 μl of DMF (5.88 mmol). The isolated residue was purified by flash column chromatography (1:9 ether/pentane) to give 154 mg of 3-chloro-4-(1-methoxy-1-methyl-ethyl)-benzaldehyde (62%) as a colorless liquid. 1H NMR (CDCl3, 300 MHz): δ 1.69 (s, 6H), 3.18 (s, 3H), 7.69 (d, J=8.2 Hz, 1H), 7.75 (dd, J=8.2 and 1.7 Hz, 1H), 7.58 (d, J=1.7 Hz, 1H), 9.97 (s, 1H).
Reaction SMILES: [CH2:1]([SH:4])[CH:2]=[CH2:3].[OH-].[Na+].C([O:9][C:10]([NH:12][N:13]([CH2:16][CH3:17])[C:14]#[N:15])=O)C.C(O)(=O)C>O>[CH2:16]([N:13]1[C:14]([S:4][CH2:1][CH:2]=[CH2:3])=[N:15][C:10]([OH:9])=[N:12]1)[CH3:17]
Reactant: CCOC(=O)NN(C#N)CC
Reactant: C=CCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: C=CCSc1nc(O)nn1CC
Yield: 42.9 %

Procedure:
244 g of allyl mercaptan is added to a solution of 132 g of sodium hydroxide in 750 ml of water, and subsequently at room temperature 514 g of 2-ethyl-2-cyanohydrazinecarboxylic acid ethyl ester is added dropwise. After one hour's refluxing, there is added to the cooled solution 198 g of glacial acetic acid. The oily phase is separated and concentrated in vacuo to dryness. There is obtained 260 g (43% of theory) of 1-ethyl-5-allylthio-3-hydroxy-1,2,4-triazole, m.p. 74°-76° C.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[O:18][CH2:19][O:20][C:13]=12.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][Cl:37])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1>C1COCC1>[Cl:37][CH2:36][CH2:35][O:34][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([NH:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[O:18][CH2:19][O:20][C:13]=34)=[N:23][CH:24]=[N:25]2)=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: Nc1ccnc2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: COc1cc2c(Nc3ccnc4c3OCO4)ncnc2cc1OCCCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
Sodium hexamethyldisilazane (1M solution in THF; 2 ml) was added dropwise to a mixture of 4-amino-2,3-methylenedioxypyridine (0.138 g), 4-chloro-7-(2-chloroethoxy)-6-methoxyquinazoline (0.272 g) and THF (5 ml) that had been cooled to 0° C. The mixture was stirred at 0° C. for 1 hour. The resultant mixture was allowed to warm to ambient temperature and was stirred for 2 hours. The reaction was quenched by the addition of glacial acetic acid (0.12 ml). The solvents were evaporated and the residue was partitioned between methylene chloride and an aqueous ammonium hydroxide solution. The organic layer was collected and concentrated to a small volume. Diethyl ether was added and a precipitate formed. The resultant solid was isolated, washed with diethyl ether and dried. There was thus obtained the title compound (0.245 g); NMR Spectrum: (DMSOd6) 3.97 (s, 3H), 4.04 (m, 2H), 4.45 (m, 2H), 6.12 (s, 2H), 7.13 (br d, 1H), 7.25 (s, 1H), 7.60 (d, 1H), 7.83 (s, 1H), 8.47 (s, 1H), 9.87 (br s, 1H); Mass Spectrum: M+H+ 375.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[CH:21]=[CH:20][S:19][CH:18]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[Cl:25][CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>CN(C=O)C>[Cl:25][CH2:26][CH2:27][CH2:28][S:29]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[CH:21]=[CH:20][S:19][CH:18]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCNCC3)n[nH]c12
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 38a. Thus, 3-(4-piperidinyl)-5-(3-thienyl)-1H-indazole-7-carboxamide hydrochloride (Intermediate 19) (25 mg, 0.076 mmol) was reacted with 3-chloropropane sulfonyl chloride (30 uL, 0.242 mmol) in DMF (4 mL) to give 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indazole-7-carboxamide, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N+:10]([O-])[C:9]=2[C:21]2[CH:26]=[CH:25][NH:24][C:23](=[O:27])[CH:22]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][C:9]=2[C:21]2[CH:26]=[CH:25][NH:24][C:23](=[O:27])[CH:22]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccc(F)cc2)c(-c2cc[nH]c(=O)c2)[n+]([O-])c1-c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClP(Cl)Cl
Product: Cn1c(-c2ccccc2)nc(-c2cc[nH]c(=O)c2)c1-c1ccc(F)cc1
Temperature: 60 °C
Yield: 40.7 %

Procedure:
To a solution of 4-[5-(4-fluorophenyl)-1-methyl-3-oxido-2-phenyl-1H-imidazol-4-yl]pyridin-2(1H)-one of Step A (56 mg, 0.155 mmol) in CHCl3 (2 mL) was added phosphorous trichloride (16 μL, 0.186 mmol) dropwise at room temperature. The reaction mixture was heated at 60° C. for 2 hours, cooled, and poured into 1N NaOH/ice solution. The aqueous layer was extracted with CH2Cl2, and the combined organic extracts were washed with H2O followed by brine. After drying over Na2SO4, the solvent was removed in vacuo. The crude material was purified by preparative thin layer chromatography (1:10 MeOH:CH2Cl2 as an eluent) to obtain 21.8 mg of the title compound.
Reaction SMILES: [H-].[Na+:2].[CH3:3][O:4][CH:5]([O:9][CH3:10])[CH2:6][C:7]#[N:8].[CH:11](OC)=[O:12]>C(OCC)C>[C:7](/[C:6](/[CH:5]([O:9][CH3:10])[O:4][CH3:3])=[CH:11]\[O-:12])#[N:8].[Na+:2]
Reactant: COC(CC#N)OC
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(OC)/C(C#N)=C/[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.2 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 2.52 g, 63.0 mmol) in diethylether (75 mL) was added 3,3-dimethoxypropanenitrile (6.17 mL, 55.0 mmol) followed by methyl formate (6.74 mL, 110 mmol). The solution was stirred for 3 days at RT. The resulting solid was collected by vacuum filtration and washed with ether to afford sodium (E)-2-cyano-3,3-dimethoxyprop-1-en-1-olate (4.2 g, 25.4 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH:4]=[C:5]([C:10]([CH2:12][O:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])=O)[C:6]([O:8][CH3:9])=[O:7].[CH2:31]([O:33][C:34](=[O:39])/[CH:35]=[C:36](\[NH2:38])/[CH3:37])[CH3:32]>CC(O)C>[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH:4]1[C:35]([C:34]([O:33][CH2:31][CH3:32])=[O:39])=[C:36]([CH3:37])[NH:38][C:10]([CH2:12][O:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]2=[O:26])=[C:5]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(=Cc1ccccc1Cl)C(=O)COCCN1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(COCCN2C(=O)c3ccccc3C2=O)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 15 °C
Reaction time: 20 h

Procedure:
87 g of methyl 2-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetate was dissolved in 102 ml of 2-propanol at 80° C. 33.1 g of ethyl-3-aminocrotonate was added and the mixture was heated at the same temperature for 16 hours. The mixture was evaporated to dryness. The residue was dissolved in 153 ml of glacial acetic acid at 80° C. The mixture was cooled to 15° C. and stirred at the same temperature for 20 hours. The solid was filtered off and washed with 78 ml of glacial acetic acid. The solid was suspended in 150 ml of methanol and agitated at 60° C. for 30 minutes. The solid was cooled to 20° C. and filtered off, washed with 30 ml of methanol and dried. The product was recrystallized from ethyl acetate.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)CC)C.[C:19](=O)([O-])[OH:20].[Na+]>CO>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:20][CH3:19])=[O:7]
Reactant: O=C(Cl)c1cccc(CBr)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
3-Bromomethylbenzoyl chloride (1.96 g, 10.37 mmol) was dissolved in methanol (20 ml), and triethylamine (1.5 ml) was added thereto. The mixture was stirred at room temperature for 1 hour. The mixture was poured into a saturated sodium hydrogencarbonate solution and was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the captioned compound (1.90 g, 10.29 mmol, yield: 97%) as a colorless oil.