Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]([NH2:24])=[O:23])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7](CC3C=CC=CC=3)[C:6]=2[N:21]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:22]([NH2:24])=[O:23])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:21]=1
Reactant: NC(=O)c1cc2c3ccccc3n(Cc3ccccc3)c2nc1N
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Temperature: 95 °C
Reaction time: 6 h

Procedure:
To a solution of 2-amino-9-benzyl-9H-pyrido[2,3-b]indole-3-carboxamide (vii-a, 1.01 g, 319 mmol) in benzene (30 mL) was added AlCl3 (1.10 g, 8.25 mmol), and the reaction was heated to 95° C. under atmosphere of Ar. After 6 h, the reaction was cooled to 0° C., quenched with water (75 mL) and poured into a separatory funnel containing EtOAc (200 mL). The mixture washed with 1N NaOH (2×200 mL) and the organic layer was dried over sodium sulfate, filtered and concentrated to yield 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide as a light brown solid (5, 319 mg, 44%). NH4OAc Standard conditions. DAD Retention Time =5.10 min. M+H=227. 1H NMR (300 MHz, DMSO-d6): δ 11.33 (br s, 1H), 8.68 (s, 1H), 7.85 (br s, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.44 (br s, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.24 (dd, J=7.3, 7.3 Hz, 1H), 7.12 (dd, J=7.9, 7.9 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.[K+].[Br-]>>[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[NH:2])=[CH:12][CH:11]=1
Reactant: N#Cc1ccncc1
Reactant: Cc1ccc(N)cc1
Agent: [Br-]
Agent: [K+]
Product: Cc1ccc(NC(=N)c2ccncc2)cc1
Yield: 72.5 %

Procedure:
The title compound was prepared from 4-cyanopyridine (9.72 g, 93 mmol) and 4-methylaniline (10 g, 93 mmol) by following the procedure described in preparation 10 (14.3 g, yield 72.5%, mp 120-123° C., purity 98.75% by HPLC). 1H-NMR (CDCl3):δ 2.33 (s, 3H), 5.06 (bs, 2H, D2O exchangeable), 6.84-6.86 (d, 2H), 7.16-7.18 (d, 2H), 7.71-7.72 (d, 2H), 8.66-8.67 (d, 2H). IR (KBr) cm−1: 3437, 3138, 1644. MS m/z:212.1 (M+).
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]([O:18]C)=[O:17])([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2].[OH-].[K+]>O.CO>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:13][CH2:12][C:11]([C:16]([OH:18])=[O:17])([CH2:14][CH2:15]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCC12CCC(C(=O)OC)(CC1)CC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)CCC12CCC(C(=O)O)(CC1)CC2
Temperature: 60 °C
Yield: 98.4 %

Procedure:
Ester 1-3 (880 mg, 3 mmol) was dissolved in 10% water/methanol solution (100 mL) and treated with 1 g of potassium hydroxide. The reaction was heated at 60° C. for 1 h then at 45° C. overnight. The mixture was concentrated in vacuo then acidified to pH 2 with 1M HCl and extracted with three portions of methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate and evaporated to give 4-[2-(ethylsulfonyl)ethyl]bicyclo[2.2.2]octane-1-carboxylic acid (1-4) (810 mg).
Reaction SMILES: [CH2:1]([N:3]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])[CH3:2].Cl.[NH2:26][CH2:27][C:28]1[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=1[CH2:34][CH2:35][CH3:36].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:1]([N:3]([CH:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:15])([F:14])[F:16])[CH:12]=1)[C:7]([NH:26][CH2:27][C:28]1[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=1[CH2:34][CH2:35][CH3:36])=[O:8])[CH3:2]
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)O)c1C)C1CCN(C)CC1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(C(F)(F)F)cc(N(CC)C2CCN(C)CC2)c1C
Temperature: 23 °C
Reaction time: 20 h
Yield: 22.4 %

Procedure:
To a stirred solution of 3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoic acid (crude material, 680 mg, 1.97 mmol) and 3-(aminomethyl)-6-methyl-4-propyl-1,2-dihydropyridin-2-one HCl salt (642 mg, 2.96 mmol) in DMSO (7 mL) was added PyBOP (1.85 g, 3.55 mmol) and hunig base (764 mg, 5.91 mmol). The reaction mixture was stirred at 23° C. for 20 hours. The reaction mixture was quenched with water and resulting precipitate was collected. The solid was purified by silica gel column chromatography (NH—SiO2 ethylacetate/MeOH=20/1) to give the titled compound as a white solid (224 mg, 22% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.31 (s, 1H), 7.26 (s, 1H), 7.16 (m, 1H), 5.94 (s, 1H), 4.55 (d, J=5.9 Hz, 2H), 3.08 (q, J=7.0 Hz, 2H), 2.82 (m, 2H), 2.66-2.73 (m, 3H), 2.33 (s, 3H), 2.24 (s×2, 6H), 1.79-1.98 (m, 2H), 1.67-1.75 (m, 4H), 1.59-1.66 (m, 2H), 1.02 (t, J=7.2 Hz, 3H), 0.84 (t, J=7.0 Hz, 3H); MS (ES) [M−H] 505.2; HPLC 98.1% purity.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6](C(OC)=O)=[CH:5][CH:4]=1.[CH3:15][Li].C([O:19][CH2:20][CH3:21])C.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:12]=[CH:11][C:6]([C:20]([OH:19])([CH3:21])[CH3:15])=[CH:5][CH:4]=1
Reactant: [Li]C
Reactant: CCOCC
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Methyl 4-(trifluoromethyl)benzoate (Compound SP825) (37.1 g, 181 mmol) was dissolved in dehydrated THF (90 ml) under a nitrogen atmosphere, a solution of methyl lithium in diethyl ether (1.5 M, 360 ml, 544 mmol) was added dropwise at 0° C. over 2 hours, and the mixture was stirred at room temperature for 30 minutes. A 50% aqueous ammonium chloride solution was slowly added, followed by extraction with ethyl acetate (200 ml×2). This was dried over sodium sulfate and then concentrated under reduced pressure, and the resulting residue was purified by Silica gel column chromatography (hexane/DCM=100/0→25/75) to afford 2-[4-(trifluoromethyl)phenyl]propan-2-ol (Compound SP824) (84%, 31.0 g).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][N:5]=[C:4]1[C:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1.Cl[CH2:14][O:15][CH3:16]>CN(C)C=O>[CH3:14][O:15][CH2:16][O:12][C:8]1([C:4]2[S:3][CH:7]=[CH:6][N:5]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: OC1(c2nccs2)CCC1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOC1(c2nccs2)CCC1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) suspension of sodium hydride (1.07 g, 44.4 mmol) in N,N-dimethylformamide (50 mL) was added a solution of 1-(thiazol-2-yl)cyclobutanol (Example 1A) (5.3 g, 34.1 mmol) in N,N-dimethylformamide (18 mL). After 0.5 hours, chloro(methoxy)methane (3.89 ml, 51.2 mmol) was added, and the reaction was stirred for 16 hours. The reaction was quenched by the addition of ether and water. The layers were separated, and the aqueous layer was extracted with additional ether. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 50% ethyl acetate in hexane, to give the title compound. MS ESI(+) m/z 200 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:32]([S:34]([Cl:37])(=[O:36])=[O:35])#[CH:33]>O1CCCC1>[ClH:37].[CH2:32]([S:34]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:8]=2)[CH2:2][CH2:3]1)(=[O:36])=[O:35])[CH3:33]
Reactant: COc1ccc(-c2cc3ccccc3c(N3CCNCC3)n2)cc1
Reactant: C#CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCN(c2nc(-c3ccc(OC)cc3)cc3ccccc23)CC1
Product: Cl
Yield: 77 %

Procedure:
1-Piperazinyl-3-(4-methoxyphenyl)isoquinoline (140 mg) was dissolved in tetrahydrofuran (2 ml), followed by the addition of triethylamine (0.12 ml) and ethynylsulfonyl chloride (0.08 ml), and the mixture was reacted for 2 hr. The reaction solution was partitioned between ethyl acetate and a 2N aqueous solution of sodium hydroxide. The resulting organic layer was washed with water and brine and dried. The resulting product was recrystallized from hexane/ethyl acetate, to give the title compound (139 mg, yield; 77%). The resulting compound was converted into an oxalate in a conventional manner, to give the oxalate of the title compound as white crystals.
Reaction SMILES: [CH2:1]([C:3]1([C:12]2[CH:13]=[C:14]([CH:49]=[CH:50][CH:51]=2)[O:15][C:16]2[CH:23]=[C:22]([CH2:24][C:25]3[N:26]=[CH:27][N:28](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:29]=3)[CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11])[CH3:2].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:67]>>[ClH:67].[CH2:1]([C:3]1([C:12]2[CH:13]=[C:14]([CH:49]=[CH:50][CH:51]=2)[O:15][C:16]2[CH:23]=[C:22]([CH2:24][C:25]3[NH:26][CH:27]=[N:28][CH:29]=3)[CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11])[CH3:2]
Reactant: ClCCl
Reactant: CCC1(c2cccc(Oc3cc(Cc4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)ccc3C#N)c2)CCCCN(C)C1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCC1(c2cccc(Oc3cc(Cc4cnc[nH]4)ccc3C#N)c2)CCCCN(C)C1=O
Product: Cl

Procedure:
2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-(1-trityl-1H-imidazol-4-ylmethyl)-benzonitrile (as described in Example 15, Step B) (0.074 g, 0.110 mmol) and triethylsilane (0.140 mL, 0.828 mmol) were stirred in CH2Cl2 (5 mL) and TFA (2.5 mL) for 1 h. The solution was concentrated in vacuo and purified using reverse phase chromatography (95/5-5/95 H2O/CH3CN with 0.1% TFA, flow=65 mL/min). The compound was converted to its free base using saturated NaHCO3 solution, extracted with CH2Cl2 (3×), dried (MgSO4), filtered and treated with 1N HCl ethereal solution to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][N:10]([CH:12]([CH3:16])[CH2:13][CH:14]=O)[CH:11]=2)[CH:2]=1.[NH:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH2:18].C(=O)([O-])[O-].[Na+].[Na+]>CC(O)=O.O.CCOC(C)=O>[CH3:23][C:22]([O:21][C:19]([NH:17][NH:18][CH2:14][CH2:13][C@H:12]([N:10]1[CH:11]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=[CH:9]1)[CH3:16])=[O:20])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(CC=O)n1cnc(-c2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@H](CCNNC(=O)OC(C)(C)C)n1cnc(-c2cccnc2)c1
Reaction time: 1 h

Procedure:
(R/S)-3-(4-pyridin-3-yl-imidazol-1-yl)-butan-1-al (11) (1 mmol) is dissolved in 10 mL HOAc and t-butyl hydrazinecarboxylate (1.1 mmol) is added. After 1 h, NaHB(OAc)3 (5 mmol) is added at 25° C. After 2 h, the reaction is poured into sodium carbonate in water and EtOAc. The water layer is removed, the organics are washed with brine, and dried over sodium sulfate. The solvent is removed in vacuo to leave the product (32).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([CH3:34])[N:29]=[CH:28]5)[C:20]3=[O:35])[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH:21]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([CH3:34])[N:29]=[CH:28]5)[C:20]3=[O:35])[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCN=C(c4ccc5c(cnn5C)c4)C3=O)sc2c1-c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCNC(c4ccc5c(cnn5C)c4)C3=O)sc2c1-c1ccc(Cl)cc1
Reaction time: 12 h

Procedure:
To the solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-5,6-dihydropyrazin-1(2H)-yl)benzo[d]thiazol-6-yl)acetate (64 mg, 0.1 mmol) in THF (1 mL) was added acetic acid (6 μL, 0.1 mmol), followed by sodium cyanoborohydride (10 mg, 0.2 mmol). The mixture was stirred for 12 hours, and diluted with ethyl acetate. Sodium hydroxide solution (1 N, 5 mL) was added, and the mixture was stirred for 30 minutes. Organic phase was separated, and was washed water and brine, and was dried over sodium sulfate. Concentration and purification with flash column chromatography (hexanes/EtOAc) gave (2S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopiperazin-1-yl)benzo[d]thiazol-6-yl)acetate. LCMS-ESI+: calc'd for C34H37ClN5O4S: 646.2 (M+H+); Found: 646.2 (M+H+).
Reaction SMILES: N1C=CC=CC=1.[C:7]1([N:13]=[C:14]=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:16][C:17]1[S:18][C:19]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[C:20]([CH3:27])[C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[CH3:27][C:20]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]([NH:16][C:14]([NH:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:15])[S:18][C:19]=1[C:28]1[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1c(N)sc(-c2ccc([N+](=O)[O-])cc2)c1C
Reactant: O=C=Nc1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(NC(=O)Nc2ccccc2)sc(-c2ccc([N+](=O)[O-])cc2)c1C
Temperature: 97.5 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
Toluene (500 ml), pyridine (12.27 g, 155.06 mmol) and phenyl isocyanate (14.58 g, 122.41 mmol) were added to ethyl 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate (25.00 g, 81.61 mmol), and the mixture was stirred at 95-100° C. for 4 hours. It was confirmed that starting materials were almost disappeared. After the reaction solution was stirred for 2 hours under ice-cooling, the crystals were isolated with a centrifuging machine and washed with cold toluene (150 ml). The crystals were dried under vacuum at 60° C. for 8 hours to give ethyl 4-methyl-5-(4-nitrophenyl)-2-(3-phenylureido)thiophene-3-carboxylate (32.42 g, 76.20 mmol, 93.4%)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](OC)=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(OC)=[O:2].[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[OH:29].F.B(F)(F)F.[C:35](=[O:38])(O)[O-].[Na+]>O>[CH3:9][C:10]1[CH:5]=[C:6]([CH:7]=[C:8]([CH3:11])[C:35]=1[OH:38])[C:17]([C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1](=[O:2])[C:26]3[CH:25]=[C:24]([CH3:28])[C:23]([OH:29])=[C:22]([CH3:21])[CH:27]=3)=[CH:10][CH:9]=2)=[CH:16][CH:15]=1)=[O:18]
Reactant: O=C([O-])O
Reactant: Cc1cccc(C)c1O
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)OC)cc2)cc1
Agent: F
Agent: FB(F)F
Agent: [Na+]
Solvent: O
Product: Cc1cc(C(=O)c2ccc(-c3ccc(C(=O)c4cc(C)c(O)c(C)c4)cc3)cc2)cc(C)c1O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
4,4'-Dicarbomethoxybiphenyl (67 g, 0.25 mole) and 2,6-dimethylphenol (61 g, 0.50 mole) were charged to a one-liter Hastalloy C® shaker tube. The tube was cooled and charged with hydrogen fluoride (200 g) and boron trifluoride (75 g). The tube was heated to 50° C. and shaken at 50° C. for 4 hr. It was then cooled and vented, and the contents, an orange solid in an orange solution, were allowed to evaporate in the hood. The orange solid that resulted was stirred in 2 l. of water, warmed, and isolated by filtration of the warm mixture. The precipitate was stirred in 2 l. of water, warmed, and neutralized with sodium bicarbonate. The solid was isolated by filtration of the warm solution, washed with water, and air dried to afford crude 4,4'-bis(3,5-dimethyl-4-hydroxybenzoyl)biphenyl in a yield of 107.6 g (96%), as a salmon-colored powder.
Reaction SMILES: C[N:2]([C:4]([C:26](=O)[CH2:27]C)=[CH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:3].O.[CH3:31][NH:32]N>CO>[CH2:26]([C:4]1[N:2]([CH3:3])[N:32]=[CH:31][C:5]=1[S:6]([C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)(=[O:7])=[O:8])[CH3:27]
Reactant: CNN
Reactant: CCC(=O)C(=CS(=O)(=O)c1ccc(OS(=O)(=O)c2ccc(C)cc2)cc1)N(C)C
Solvent: O
Solvent: CO
Product: CCc1c(S(=O)(=O)c2ccc(O)cc2)cnn1C
Temperature: 25 °C
Yield: 43.2 %

Procedure:
A mixture composed of 4.3 g (0.01 mole) of 1-(N,N-dimethylamino)-1propionyl 2-(4-tosyloxybenzenesulfonyl)ethene is heated at reflux for 20 hours in 25 ml of methanol and 10 ml of water in the presence of 2.35 g (0.05 mole) of methylhydrazine. The mixture is allowed to cool to room temperature and then cooled in ice for 1 h. It is evaporated to dryness and 4.85 g of residue are thus obtained which are recrystallized from 250 ml of water and decolorized with 0.8 g of active charcoal. The product is filtered off and allowed to crystallize for 2 hours in ice. It is recrystallized again from 50 ml of dichloroethene. In this manner, 1.15 g of 5-ethyl 4-(4-hydroxybenzenesulfonyl)1-methyl pyrazole is obtained which represents a yield of 43.2%. M.p.: 188.5°-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][F:19]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:17][CH2:18][F:19])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: FCCBr
Reactant: N#CC(C#N)Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCF)Cc1ccc(Cl)cc1
Yield: 24.2 %

Procedure:
Using 1.00 g of (4-chlorobenzyl)malononitrile, 10 ml of N,N-dimethylformamide, 0.21 g of sodium hydride (60% in oil), and 0.67 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.30 g of 2-(4-chlorobenzyl)-2-(2-fluoroethyl)malononitrile (the present compound (24)).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9](=[N:11]C1CCCCC1)C.O1CCC[CH2:19]1>>[OH:8][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:19])[CH:9]=[NH:11]
Reactant: CC=NC1CCCCC1
Reactant: O=Cc1ccccc1
Reactant: C1CCOC1
Product: CC(O)(C=N)c1ccccc1

Procedure:
The direct aldol condensation also takes place by reacting the benzaldehyde derivative with the anion of an N-substituted ethylideneamine, for example ethylidenecyclohexylamine. The reaction, which is preferably carried out in the cold in an aprotic solvent, for example tetrahydrofuran, provides a β-hydroxy-β-phenylpropylideneamine which, with simultaneous dehydration and imine hydrolysis in an acidic medium, for example in dilute hydrochloric acid, gives the corresponding cinnamaldehyde (G. Wittig and A. Hesse, Org. Synth., 50, 67).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[N:12]S(C(C)(C)C)=O.Cl>O1CCOCC1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[NH:12]
Reactant: CC(C)(C)S(=O)N=C1CCOc2ccc(Br)cc21
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N=C1CCOc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
N-(6-Bromochroman-4-ylidene)-2-methylpropane-2-sulfinamide (2.0 g, 6.0 mmol, Intermediate 1) was dissolved in dry dioxane (2 mL), and 4M HCl in dioxane (15 mL, 60.00 mmol) was added. A white precipitate started to form. The mixture was stirred at r.t. for 12 h. The mixture was diluted with dry Et2O (50 mL) and vacuum filtered. The filter cake was washed with dry Et2O (50 mL), then immediately dissolved by shaking in NaHCO3 (aq) and CH2Cl2. The organic phase was dried (K2CO3) and evaporated to give 6-bromochroman-4-imine (1.3 g, 5.7 mmol). The solid was dissolved together with 2-oxopropanethioamide (Intermediate 2, 1.7 g, 17 mmol, Intermediate 2) in dry methanol (5 mL) and the resulting solution was heated at 60° C. for 12 h. Evaporation onto silica and purification by flash chromatography (EtOAc in heptane) gave the title compound (0.39 g, 21% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.18 (m, 1H), 2.35 (m, 1H), 2.42 (s, 3H), 4.35-4.40 (m, 1H), 4.60 (m, 1H), 6.81 (d, 1H), 6.88 (d, 1H), 7.33 (dd, 1H); MS (ES+) m/z 311 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[Cl:19]NC(=O)CCC(N)=O.O.C(OCC)(=O)C>CN(C=O)C>[Cl:19][C:3]1[C:2]([OH:1])=[N:7][C:6]2[N:8]([CH:11]([CH3:13])[CH3:12])[N:9]=[CH:10][C:5]=2[C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: NC(=O)CCC(=O)NCl
Reactant: CCOC(=O)c1cc(O)nc2c1cnn2C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(Cl)c(O)nc2c1cnn2C(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To a stirred solution of ethyl 6-hydroxy-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1.3 g, 5.2 mmol) in DMF (7 mL), N-chlorosuccinamide (1.11 g, 8.35 mmol) was added. The resulting reaction mixture was stirred at 60° C. for 1 h. On completion of reaction, water was added to it and extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate (1 g, 69.9%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[N:5]([C:13]([CH3:18])([CH3:17])[C:14]([O-:16])=O)=[N:6][C:7]([CH3:12])([CH3:11])[C:8]([O-:10])=O.C[O-].[Na+].O>CO>[N:6]([C:7]([CH3:11])([CH3:12])[C:8]([NH:4][CH2:1][CH2:2][CH3:3])=[O:10])=[N:5][C:13]([CH3:18])([CH3:17])[C:14]([NH:4][CH2:1][CH2:2][CH3:3])=[O:16]
Reactant: CCCN
Reactant: CC(C)(N=NC(C)(C)C(=O)[O-])C(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCNC(=O)C(C)(C)N=NC(C)(C)C(=O)NCCC
Temperature: 5 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
28.3 Grams of propylamine is mixed with 50 g of 2,2'-azobis (2-methyl propionate), and 10 g of 28% sodium methoxide solution in methanol and 10 ml of methanol are added thereto with stirring, followed by conducting a reaction at room temperature with stirring for 6 hours and keeping standing overnight. 100 Milliliter of water is added to the reaction solution and cooled to 5° C. to precipitate crystals. The crystals are recovered by filtration and dried to give 54.0 g (yield: 87%) of 2,2'-azobis(N-propyl-2-methyl propionamide) as pale yellow crystal. The solubility is shown in Table 1.