Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][CH3:23])[C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24](=O)[CH3:25].C([BH3-])#N.[Na+].O>CO.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][CH3:23])[C:15]2[C:20]([NH:21][CH2:24][CH3:25])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=O
Reactant: CCN(c1ncccc1N)C1CCN(Cc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCNc1cccnc1N(CC)C1CCN(Cc2ccccc2)CC1
Reaction time: 18 h

Procedure:
1-Benzyl-4-[N-ethyl-N-(3-(amino)-2-pyridinyl)amino]piperidine (EXAMPLE 204 Part B, 1.0 g, 3.22 mmol) is dissolved in methanol (8 ml) and cooled to 0°. The acetaldehyde (0.20 ml, 3.54 mmol) and sodium cyanoborohydride (0.31 g, 3.54 mmol) are added and the reaction is slowly warmed to 20°-25° and stirred for 18 hr. Then a further sodium cyanoborohydride (2 eq.) and 1.6 eq. of acetaldehyde are added and the reaction is stirred a further 20 hr. Then it is diluted with ethyl acetate and poured into water, washed with saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (silica gel; methanol/methylene chloride (2.5/97.5)), gives the title compound, NMR (300 MHz, CDCl3) 7.65, 7.40-7.17, 6.83, 6.71, 4.63, 3.42, 3.10-3.00, 2.93, 2.81, 1.92, 1.72-1.51, 1.17 and 079δ.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([CH3:29])=[CH:27][S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[C:28]([CH3:29])=[CH:27][S:26][C:16]=2[N:17]=1
Reactant: Cc1csc2nc(-c3cnccn3)nc(Cl)c12
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1csc2nc(-c3cnccn3)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)([CH2:22][CH2:23]O)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:33][C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)([CH2:22][CH2:23][N:36]4[CH2:37][CH2:38][C@H:34]([F:33])[CH2:35]4)[O:18][C:17]3=[O:32])[CH3:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: F[C@H]1CCNC1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCN2CC[C@H](F)C2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 178 using (S)-3-fluoropyrrolidine in Step 2. LC-MS Method 3 tR=0.962 min, m/z=531.1; 1H NMR (CDCl3) 0.80-0.92 (m, 1H), 1.46-1.57 (m, 4H), 1.59 (s, 3H), 2.16-2.40 (m, 6H), 2.75-3.09 (m, 3H), 5.10-5.38 (m, 1H), 5.70 (m, 1H), 7.01-7.13 (m, 6H), 7.30-7.49 (m, 4H), 7.46 (m, 2H).
Reaction SMILES: CS(C)=[O:3].C([O-])([O-])=O.[K+].[K+].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][C:26]([O:32][CH2:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:27][CH:28]=3)[CH2:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)#[N:12].OO>CO.O>[N:36]1([CH2:35][CH2:34][CH2:33][O:32][C:26]2[CH:25]=[C:24]3[C:29]([CH2:30][CH2:31][N:22]([S:19]([C:16]4[CH:17]=[CH:18][C:13]([C:11]([NH2:12])=[O:3])=[CH:14][CH:15]=4)(=[O:20])=[O:21])[CH2:23]3)=[CH:28][CH:27]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CS(C)=O
Reactant: N#Cc1ccc(S(=O)(=O)N2CCc3ccc(OCCCN4CCCCC4)cc3C2)cc1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: NC(=O)c1ccc(S(=O)(=O)N2CCc3ccc(OCCCN4CCCCC4)cc3C2)cc1
Yield: 26 %

Procedure:
A 1.4 mL DMSO mixture of K2CO3 is stirred under N2, 2-(4-cyanobenzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline (75 mg, 0.17 mmol) is added, 0.2 mL H2O added, followed by 30% H2O2 (1.4 mL, 12 mmol) and reaction is stirred at room temperature for 4 hours. The reaction mixture is diluted with MeOH, filtered, and the solids washed twice with MeOH. The filtrate is concentrated and the residue is purified by chromatography (SCX-MeOH wash, elute 2M NH3/MeOH; then SiO2; 0-10% MeOH/CH2Cl2/1% NH4OH gradient) to give the product as an off-white solid (26 mg, 26% yld). MS (ES+)458.2(M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15](=[N:24][NH2:25])[NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[Cl:23])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[N:27]#[C:28]Br>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:16]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[Cl:23])[C:28]([NH2:27])=[N:25][N:24]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1
Reactant: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: N#CBr
Solvent: CO
Product: Nc1nnc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n1-c1ccccc1Cl
Temperature: 45 °C
Yield: 21 %

Procedure:
A solution of crude 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbohydrazonamide (195, 0.434) in methanol (5 mL) was treated with a solution of cyanogen bromide (115 mg, 1.1 mmol) in methanol (1 mL) at room temperature. The reaction vessel was sealed and heated at 45° C. for 2 h, cooled to room temperature, quenched upon addition of saturated sodium bicarbonate and extracted with ethylacetate. The combined organics were dried over sodium sulfate and concentrated and the residue purified by flash column chromatography (1-10% MeOH in methylene chloride to give 287 (43 mg, 21% yield). MS (ESI): 475.0
Reaction SMILES: [CH:1]1([N:7]([CH2:29][CH2:30][O:31]C(=O)C)[C:8](=[O:28])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]2[NH:23][C:24](=[O:27])[C:25](=[CH2:26])[N:17]2[CH2:16]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([N:7]([CH2:29][CH2:30][OH:31])[C:8](=[O:28])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]2[NH:23][C:24](=[O:27])[C:25](=[CH2:26])[N:17]2[CH2:16]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=c1c(=O)[nH]c2n1Cc1cc(OCCCC(=O)N(CCOC(C)=O)C3CCCCC3)ccc1N=2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=c1c(=O)[nH]c2n1Cc1cc(OCCCC(=O)N(CCO)C3CCCCC3)ccc1N=2
Reaction time: 0.5 h

Procedure:
To a solution of N-cyclohexyl-N-(2-acetoxyethyl)-4-(2-oxo-3-methylene-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutanamide 50 mg in ethanol (20 ml) was added 3N NaOH (5 ml) in small portions. After 30 minutes at room temperature, the reaction mixture was neutralized with concentrated HCl and the resulting precipitate was collected by filtration and dried to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:15][N:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]2=[O:16])=[CH:11][CH:10]=[C:9]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:8]=3)[NH:4][CH2:3]1.[H-].[Na+].[CH3:28]I>C1COCC1>[CH3:28][N:4]1[C:5]2=[N:6][C:7]3[C:12]([C:13](=[O:16])[N:14]2[CH2:15][C:2]([CH3:25])([CH3:1])[CH2:3]1)=[CH:11][CH:10]=[C:9]([C:17]#[C:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH:8]=3
Reactant: CC1(C)CNc2nc3cc(C#Cc4ccccn4)ccc3c(=O)n2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC(C)(C)Cn2c1nc1cc(C#Cc3ccccn3)ccc1c2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.7 %

Procedure:
A mixture of 3,3-dimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrimido[2,1-b]quinazolin-6(2H)-one (30 mg, 0.09 mmol), NaH (14 mg, 0.36 mmol) and MeI (28 mg, 0.2 mmol) in dry THF was stirred for 24 h at room temperature. Then the solvent was evaporated to give the crude product, which was purified by column chromatography to give 3 mg of the title compound. MS (ESI): 345 (MH+). 1H NMR (300 MHz, CDCl3) δ 8.66-8.65 (d, J=4.8 Hz, 1H), 8.08-8.05 (d, J=8.2 Hz, 1H), 7.75-7.69 (td, J=7.8, 1.8 Hz, 1H), 7.60-7.55 (m, 2H), 7.31-7.30 (m, 2H), 3.82 (s, 2H), 3.28 (s, 3H), 3.18 (s, 2H), 1.13 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[S:14]1[CH2:18][C:17](=[O:19])[NH:16][C:15]1=[O:20]>>[OH:11][C:10]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH:6]=[C:18]2[S:14][C:15](=[O:20])[NH:16][C:17]2=[O:19])=[CH:8][C:9]=1[O:12][CH3:13]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: O=C1CSC(=O)N1
Product: COc1cc(C=C2SC(=O)NC2=O)cc(OC)c1O
Yield: 24.2 %

Procedure:
Prepared according to the procedure described in Example 1 using 3,5-dimethoxy-4-hydroxybenzaldehyde (4.8 g, 26 mmoles) and 2,4-thiazolidinedione (2.9 g, 25 mmoles). Recrystallization from methanol gave the pure product (1.7 g), mp 248°-249° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:22])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[Sn].Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:22])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(NC(=O)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl
Agent: [Sn]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(N)c2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
A solution of 4-(3-nitro-benzoylamino)-benzoic acid ethyl ester (0.50 g, 1.59 mmol) in THF (5.0 ml) was treated with tin metal (0.38 g, 3.18 mmol) and 6N HCl (2.5 ml). The mixture was warmed to 50° C. and stirred for 30 min. After cooling to room temperature, the solvent was evaporated, and the residue treated with 10% aqueous NaOH (10.0 ml). The resulting suspension was filtered, washing with water. The solid was dissolved in THF and treated with Na2SO4. After filtration, the filtrate was evaporated to yield 4-(3-amino-benzoylamino)-benzoic acid ethyl ester (0.36 g, 80%) as a light yellow solid, MS (ISP): m/e=285.3 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[C:24]([C:30]4[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=4)=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[C:24]([C:30]4[CH:31]=[CH:32][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:35]=4)=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[O:22])=[CH:18][CH:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: Cc1ccc(C(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(-c2ccc(C(C)C)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)Nc2ccc(N3CCNCC3)cc2)c(-c2ccc(C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
To a solution of 4-{4-[(4′-isopropyl-5-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (4 g) in CH2Cl2 (20 mL) was added trifluoroacetic acid (15 mL) and the solution was stirred at room temperature for 16 hours. The mixture was then evaporated under reduced pressure and the residue was taken in water and basified with a 1N NaOH aqueous solution. The resulting precipitate was extracted with CH2Cl2 and the organic phase was washed with water, dried over Na2SO4 filtered and evaporated to give the title compound (3 g) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:21]1([S:27]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([C:6]([N:8]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])=[CH:4][CH:3]=2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(NS(=O)(=O)c2ccccc2)cc1)N1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g), phenylsulfonyl chloride (0.29 ml), triethylamine (0.32 ml) and dichloromethane (30 ml) is stirred at room temperature overnight. The reaction mixture is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from methanol/diethyl ether to give 1-(4-phenylsulfonylaminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.27 g) as colorless prisms, m.p. 178°-182.5° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH:16]([CH2:47]Br)[CH2:17][C:18]1[CH:19]=[C:20]2[C:26]3([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]3)[CH2:25][N:24]([C:38]([O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])=[O:39])[C:21]2=[CH:22][CH:23]=1.O>CN(C)C=O>[CH2:12]([O:11][C:3]([C:4]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:15][CH:16]([CH2:17][C:18]2[CH:19]=[C:20]3[C:26]4([CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]4)[CH2:25][N:24]([C:38]([O:40][CH2:41][CH2:42][Si:43]([CH3:45])([CH3:46])[CH3:44])=[O:39])[C:21]3=[CH:22][CH:23]=2)[CH2:47]1)=[O:10])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CC(CBr)CBr)cc12
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CC(Cc2ccc3c(c2)C2(CCN(C(=O)OC(C)(C)C)C2)CN3C(=O)OCC[Si](C)(C)C)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
Sodium hydride (10.0 mg, 0.21 mmol) was dissolved in N,N-dimethylformamide (1 mL). Thereafter, diethyl malonate (13.0 μL, 0.086 mmol) was added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at 100° C. for 30 minutes. Thereafter, an N,N-dimethylformamide (0.5 mL) solution of 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(3-bromo-2-(bromomethyl)propyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (51.1 mg, 0.080 mmol) was further added to the reaction solution under cooling on ice, and the thus obtained mixture was then stirred at 100° C. for 2 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate=5:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-((3,3-bis(ethoxycarbonyl)cyclobutyl)methyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (20.8 mg, 41%) in the form of a colorless oily product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH:9]([C:11](=[O:30])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:15][C:14]=2[F:29])[NH:8][N:7]=1)=[O:5])[CH3:2].N1C=CC=CC=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[O:46])=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH:9]([C:11](=[O:30])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:15][C:14]=2[F:29])[N:8]([C:45](=[O:46])[NH:44][C:41]2[CH:42]=[CH:43][C:38]([Cl:37])=[CH:39][CH:40]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=NNC(C(=O)Nc2ccc(-c3ccccc3S(C)(=O)=O)cc2F)C1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1=NN(C(=O)Nc2ccc(Cl)cc2)C(C(=O)Nc2ccc(-c3ccccc3S(C)(=O)=O)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester (1.520 g) in methylene chloride (12 ml) was added pyridine (4 equiv.) and 4-chlorophenyl isocyanate (1.25 equiv.). Stirred at room temperature for 16 hours. Evaporated and recorded crude 1H: 80156×134RM1—revealed expected product and relatively clean. Purified by silica gel chromatography, eluant 10-100% EtOAc in hexane over 25 mins. Collected 1-(4-chloro-phenylcarbamoyl)-5-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester (1.480 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.Cl.[CH:29]([N:32]([CH:36](C)C)[CH2:33]CCl)(C)[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:33][N:32]([CH3:36])[CH2:29][CH2:30][N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2)[C:5]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:19][CH2:20]2)=[C:6]([C:13]#[N:14])[C:7]1=[O:12]
Reactant: Cc1ccc2[nH]c(=O)c(C#N)c(N3CCN(C(=O)c4cccs4)CC3)c2c1
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3cccs3)CC1)c(C#N)c(=O)n2CCN(C)C
Temperature: 0 °C
Yield: 34.5 %

Procedure:
A solution of Compound 107 (1 g, 2.64 mmol), 2-(diisopropylamino)ethyl chloride hydrochloride (2.64 g, 13.2 mmol), and potassium carbonate (3.64 g, 26.4 mmol) in DMF was heated overnight at 90° C. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried. The crude product was purified by flash chromatography eluting with 0-10% methanol in ethylacetate gradient to yield 409 mg (30%) of pale yellow solids. M.P. 110-117° C. 1H NMR (DMSO-d6): δ 0.93 (s, 12H), 2.40 (s, 3H), 2.59 (m, 2H), 3.01 (m, 2H), 3.61 (m, 4H), 3.91 (m, 4H), 4.15 (m, 2H), 7.16 (dd, J=3.4, 4.8 Hz, 1H), 7.49 (m, 2H), 7.58 (m, 1H), 7.69 (s, 1H), 7.80 (d, J=5.2 Hz, 1H). EIMS m/z 506 (M+1). Anal. (C28H35N5O2S) C,H, N.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][C:37]([Cl:43])=[C:38]([CH:42]=1)[C:39](Cl)=[O:40])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][C:37]([Cl:43])=[C:38]([C:39]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:40])[CH:42]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Cl)c1cc(OCc2ccccc2)ccc1Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5ccccc5)ccc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 5-(benzyloxy)-2-chlorobenzoyl chloride (compound F3) as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:13])[CH3:12].[Cl:17]N1C(=O)CCC1=O.C1C=CC=CC=1>CCCCCC>[CH3:8][C:4]1[CH:5]=[C:6]([Cl:17])[CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:12])[CH3:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cccc(C)c1N[C@H](C(=O)O)C(C)C
Solvent: CCCCCC
Solvent: c1ccccc1
Product: Cc1cc(Cl)cc(C)c1N[C@H](C(=O)O)C(C)C
Reaction time: 8 h

Procedure:
A mixture of 0.5 g of the m-phenoxybenzyl ester of N-(2,6-dimethylphenyl)valine, 0.21 g of N-chlorosuccinimide and 3 ml of benzene is heated at reflux for 2 hours. The reaction is diluted with hexane, washed with water (2×) and solvent stripped to give the crude product. To the crude product is added 0.1 g of N-chlorosuccinimide and 3 ml benzene. The mixture is heated at reflux for 30 min and then allowed to stand overnight at RT. The reaction is worked up by diluting with hexane, washing with water and stripping off solvent to yield the m-phenoxybenzyl ester of N-(2,6-dimethyl-4-chlorophenyl)valine, MS m/e 437.1 (M+, 15.3).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:3]4[N:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:29][CH2:28]3)[S:25][CH:26]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnn1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 44.3 %

Procedure:
A solution of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (200 mg, 0.793 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (181 mg, 0.739 mmol), diisopropylethylamine (0.129 ml, 0.739 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the desired product (120 mg, 44.3%) as a solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=C[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C=O.[ClH:12].OP(O)(O)=O.CCO[CH2:21][CH3:22]>C(O)(=O)C>[Cl:12][CH2:6][C:7]1[CH:8]=[C:9]2[C:4](=[CH:21][CH:22]=1)[CH2:3][CH2:2][CH2:1]2
Reactant: Cl
Reactant: CCOCC
Reactant: c1ccc2c(c1)CCC2
Agent: C=O
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: ClCc1ccc2c(c1)CCC2
Temperature: 95 °C

Procedure:
A mixture of indan (50.0 g, 0.423 mol), paraformaldehyde (23.3 g), concentrated HCl (74 mL), 85% H3PO4 (33 mL), and acetic acid (54 mL) was heated at 95° C. for 6 hours. The mixture was cooled and diluted with ether (200 mL). The organic phase was separated and washed with H2O (2×200 mL), saturated aqueous NaHCO3 (200 mL), H2O (200 mL), dried (MgSO4), and concentrated. The crude product was distilled under high vacuum (0.8 mm) to give 35.2 g (50%) as a colorless oil, b.p. 89° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]=[CH2:10])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[NH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:3]([CH3:5])=[CH:2][C:1]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6]
Reactant: C=CCOC(=O)CC(C)=O
Reactant: C1CCNC1
Product: C=CCOC(=O)C=C(C)C1CCCN1

Procedure:
Allyl 3-tetrahydropyrrolyl-2-butenoate was prepared (4.7 g, 68%) in the same manner as described in the above Example 1 (1) from allyl acetoacetate (5.0 g, 35.17 mmol) and pyrrolidine (8.8 mL, 105.51 mmol), and the obtained product was identified with the following 1H NMR data.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.S1C=CN=[C:12]1[CH:16]=O.[O:18]([CH3:20])[Na]>C1COCC1>[C:5]1([CH:3]=[CH:2][C:20]([C:16]2[CH:12]=[CH:6][CH:5]=[CH:3][CH:2]=2)=[O:18])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1nccs1
Reactant: O=C(CO)c1ccccc1
Reactant: CO[Na]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 27 %

Procedure:
2.29 g (16.8 mmol) of 2-hydroxyacetophenone, 1.8 g of thiazole-2-carbaldehyde (15.9 mmol), and 10 ml of 25% wt NaOCH3 were reacted in 50 ml of dry THF to give 0.254 g (27%) of chalcone after purification. 1H NMR (300 MHz, CDCl3): δ 12.62 (s, 1H), 8.08-7.94 (m, 4H), 7.57-7.51 (m, 2H), 7.06 (d, d, J=1.2, 8.4 Hz, 1H), 6.98 (d, d, d, J=1.2, 7.2, 8.1 Hz, 1H).