Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]#[C:20][CH2:21][O:22][CH3:23])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:24](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:42][S:43]([C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1)(=[O:45])=[O:44].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]#[C:20][CH2:21][O:22][CH3:23])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:24]([C:49]2[CH:50]=[CH:51][C:46]([S:43]([CH3:42])(=[O:45])=[O:44])=[CH:47][CH:48]=2)=[CH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COCC#Cc1cnc2c(c1)cc(C(=CC1CCCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCC#Cc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 45.5 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-[1-benzenesulfonyl-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-cyclopentyl-vinyl ester (900 mg, 1.53 mmol), 4-(methanesulfonyl)phenylboronic acid (763 mg, 3.81 mmol) and dichlorobis(triphenylphosphine)palladium (II) (107 mg, 0.15 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 1.9 mL). The mixture was subjected to microwave irradiation for 1 h at 100° C. The resulting mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine (400 mg, 45.6%) as an orange oil: LC/MS m/e calcd for C31H30N2O5S2 [M+H]+ 575.72, observed 575.1.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.Cl[CH2:18]OC.O>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[CH2:18]1
Reactant: COCCl
Reactant: Clc1ccccc1CNCCc1cccs1
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: Clc1ccccc1CN1CCc2sccc2C1
Temperature: 60 °C
Yield: 148.9 %

Procedure:
To a solution of 50.8 g (0.2 M) N-(2-chloro-benzyl)-2-(2-thienyl)-ethylamine in 70 ml dimethylformamide heated at 60° C. is added, over 7 minutes, 22.7 g (0.24 M) chloromethylmethylether. The temperature of the reaction medium is maintained at 60° C. throughout the addition step by cooling with water. Thirty minutes after completion of the chloromethylmethylether addition, the medium is cooled to 20° C. The desired product, which has precipitated out, is filtered and washed with 2×70 ml acetone, to give 45.1 g 5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine hydrochloride (Yield: 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([OH:19])[CH:16]=[CH:17]3)=[C:12]([C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:11]=2[CH2:26][C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:9])=[CH:4][CH:3]=1.[CH3:35][O:36][C:37]1[N:42]=[C:41]([CH2:43]O)[CH:40]=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([O:19][CH2:43][C:41]4[CH:40]=[CH:39][CH:38]=[C:37]([O:36][CH3:35])[N:42]=4)[CH:16]=[CH:17]3)=[C:12]([C:20](=[O:25])[C:21]([CH3:23])([CH3:24])[CH3:22])[C:11]=2[CH2:26][C:27]([CH3:33])([CH3:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:9])=[CH:6][CH:7]=1
Reactant: COc1cccc(CO)n1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(O)ccn2c1C(=O)c1ccc(Cl)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(OCc3cccc(OC)n3)ccn2c1C(=O)c1ccc(Cl)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
To a cold (0° C.) solution of ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-hydroxyindolizin-2-yl}-2,2-dimethylpropanoate (100 mg, 0.21 mmol), (6-methoxy-pyridin-2-yl)-methanol (35 mg, 0.25 mmol), and triphenylphosphine (65 mg, 0.25 mmol) in THF (5 mL) is added DIAD (48 μL, 0.25 mmol). The reaction is allowed to gradually warm to 23° C. and then stirred overnight. Silica gel is added and the mixture is concentrated in vacuo then purified by flash chromatography (SiO2, hexanes to 15% EtOAc in hexanes) to give ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-[(6-methoxypyridin-2-yl)methoxy]indolizin-2-yl}-2,2-dimethylpropanoate (20 mg, 16%).
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O[CH:24](OCC)[CH2:25][NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])C.Cl>CO.O>[CH2:30]([O:29][C:27]([NH:26][CH2:25][CH:24]1[C:13]2[NH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]=2[CH2:11][CH2:10][N:9]1[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: c1ccc(CNCCc2c[nH]c3ccccc23)cc1
Reactant: CCOC(CNC(=O)OCc1ccccc1)OCC
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C(NCC1c2[nH]c3ccccc3c2CCN1Cc1ccccc1)OCc1ccccc1
Yield: 62 %

Procedure:
To a solution of 50 g of N-benzyl-tryptamine hydrochloride (i.e., 3-(2-(benzylamino)-ethyl)indole hydrochloride) in 500 ml of methanol-water (4:1) are added 57.9 g of N-benzyloxycarbonyl-aminoacetaldehyde diethylacetal and 25 ml of 10% hydrochloric acid, and the mixture is refluxed for 16 hours. After the reaction, the reaction mixture is evaporated under reduced pressure to remove solvent, and the resultant crystals are collected by filtration. After being washed with water and ether, said crystals are added to a saturated sodium bicarbonate solution, and then extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove solvent. The residue (oil, 60 g) is purified by silica gel chromatography (Solvent: chloroform-methanol (20:1)). 46 g of 1,2,3,4-tetrahydro-1-((N-benzyloxycarbonylamino)methyl)-2-benzyl-β-carboline are thereby obtained as a caramel. Yield: 62%
Reaction SMILES: Cl[C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[C:14]#[N:15].Cl.[NH:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][O:25][C:24]2=[O:33])[CH2:19][CH2:18]1>>[C:14]([C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:2]=1[N:17]1[CH2:18][CH2:19][CH:20]([N:23]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][O:25][C:24]2=[O:33])[CH2:21][CH2:22]1)[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])=[O:7])#[N:15]
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Reactant: CC(C)NC(=O)c1ccc(Cl)c(C#N)c1
Agent: Cl
Product: CC(C)NC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(C#N)c1

Procedure:
The title compound was prepared from the product of step (iii) (0.29 g) and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.3 g) using the method of example 115 step (ii). Yield 0.073 g.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C1(C#N)CCCC1.C1([Li])C=CC=CC=1.C(OCCCC)CCC.[BH4-].[Na+].[NH2:35][CH:36]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:37]1(N(C)C)[CH2:41][CH2:40][CH2:39][CH2:38]1>C1COCC1.CO>[NH2:35][CH:36]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:37]1([CH2:1][NH:2][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Reactant: CN(Cc1ccccc1)C1(C#N)CCCC1
Agent: [BH4-]
Agent: [Li]c1ccccc1
Agent: [Na+]
Solvent: CCCCOCCCC
Solvent: C1CCOC1
Solvent: CO
Product: NC(c1ccccc1)C1(CNCc2ccccc2)CCCC1
Yield: 47 %

Procedure:
The title compound (3.90 g; 47%) was prepared from 1-[methyl(phenylmethyl)amino]cyclopentanecarbonitrile D28 (6.0 g; 28 mmol) and phenyllithium in di-n-butylether (16.21 ml of 1.9M solution; 30.8 mmol) in THF (60 ml), followed by reaction with sodium borohydride (3.2 g; 84 mmol) in methanol (60 ml) in a similar manner to that described in D2. Mass Spectrum (Electrospray LC/MS), API+: Found 295 (MH+). C20H26N2 requires 294. Ret. time 2.12 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:14]([C:13]2[CH:19]=[CH:20][C:10]([F:9])=[CH:11][CH:12]=2)=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: CCOC(=O)c1ccc(F)cc1
Product: O=C(Cc1ccnc(Cl)c1)c1ccc(F)cc1

Procedure:
Following a similar procedure to that described in reference example 19, but starting from 2-chloro-4-methylpyridine and ethyl 4-fluorobenzoate, the title compound was obtained.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:25][NH:26][C:27](=[O:36])[CH:28]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:29](O)=[O:30]>>[C:32]([CH:28]([C:29]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:30])[C:27]([NH:26][CH2:25][C:24]1[CH:23]=[C:22]([F:21])[CH:39]=[C:38]([F:40])[CH:37]=1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)C(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: CN1C(=O)C(NC(=O)C(C(=O)NCc2cc(F)cc(F)c2)C(C)(C)C)N=C(c2ccccc2)c2ccccc21

Procedure:
The title compound, MS: m/e=533.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and N-(3,5-difluoro-benzyl)-2-tert-butyl-malonamic acid.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].Cl.[NH:6]1[CH2:11][CH2:10][C:9](=[CH:12][C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)[CH2:8][CH2:7]1>C1(C)C=CC=CC=1.C(N(C(C)C)CC)(C)C.ClCCl>[F:26][C:23]([F:24])([F:25])[C:20]1[CH:21]=[CH:22][C:17]([O:16][C:15]2[CH:14]=[C:13]([CH:29]=[CH:28][CH:27]=2)[CH:12]=[C:9]2[CH2:8][CH2:7][N:6]([C:1]([Cl:4])=[O:2])[CH2:11][CH2:10]2)=[N:18][CH:19]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Cl)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round-bottomed flask was fitted with a stirring bar and dropping funnel. To the reaction flask was added dichloromethane (30 mL) and the vessel was set to chill in an ice/water bath. To the flask was added 19% v/v phosgene in toluene (6 mL). 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (3.34 g, 9 mmol, from Example 1a, Step 5) was dissolved in a 15% v/v solution of diisopropylethylamine in dichloromethane and added to the chilled reaction flask slowly using the dropping funnel. Upon addition, the solution was stirred at 0° C. for 1 h. Upon completion of the reaction, the solvent and excess phosgene were removed in vacuo. A 0.2 M stock solution of the residue in dichloroethane was prepared for use in the next step (45 mL).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:18]=[O:19])[C:12]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[C:26]2=[N:27][CH:28]=[C:29]([C:31]#[N:32])[CH:30]=[C:25]2[CH:24]=[CH:23]1.CO.[OH-].[K+]>O>[CH2:1]([O:8][C:9](=[O:21])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:18]([C:24]2[C:25]3[C:26](=[N:27][CH:28]=[C:29]([C:31]#[N:32])[CH:30]=3)[NH:22][CH:23]=2)[OH:19])[C:12]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Reactant: N#Cc1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1cnc2[nH]cc(C(O)c3c(F)ccc(NC(=O)OCc4ccccc4)c3F)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
Into a reaction vessel, (2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (25, 10.00 g, 34.3 mmol), 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (13, 4.91 g, 34.3 mmol), 50.00 mL of anhydrous methanol, and potassium hydroxide (2.77 g, 49.4 mmol) were added under nitrogen and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 500 mL of water and extracted with 3×500 mL of ethyl acetate. The organic layers were combined and dried over magnesium sulfate, filtered, and the filtrate concentrated under vacuum. The resulting residue was purified using silica gel column chromatography to provide the desired compounds (26, 4.62 g, 31%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[CH3:8][CH:9]1[CH2:14][NH:13][CH2:12][CH:11]([CH3:15])[NH:10]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:7][C:4]1[S:3][C:2]([N:13]2[CH2:12][CH:11]([CH3:15])[NH:10][CH:9]([CH3:8])[CH2:14]2)=[N:6][CH:5]=1
Reactant: Brc1cnc(Br)s1
Reactant: CC1CNCC(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(c2ncc(Br)s2)CC(C)N1
Temperature: 60 °C
Reaction time: 6 h
Yield: 64.4 %

Procedure:
A mixture of 2,5-dibromothiazole (29.5 g), 2,6-dimethyl piperazine (13.8 g), potassium carbonate (20.1 g) and dimethylformamide (150 mL) was stirred at 60° C. for 6 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure to give the title compound (21.5 g). Yield: 64%.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]#[N:25])[N:21]=[C:20]([Cl:26])[N:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[NH2:28][OH:29]>CO.CCOC(C)=O>[NH2:25]/[C:24](=[N:28]\[OH:29])/[C:22]1[N:21]=[C:20]([Cl:26])[N:19]=[C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[CH2:13][CH2:14]2)[CH:23]=1
Reactant: NO
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C#N)nc(Cl)n3)CC2)c(Cl)c1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(/C(N)=N/O)nc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 80 °C
Yield: 33 %

Procedure:
3,4-Dichloro-N-[1-(2-chloro-6-cyanopyrimidin-4-yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 199, 150 mg, 0.36 mmol), hydroxylamine hydrochloride (25 mg, 0.36 mmol) and TEA (0.05 ml, 0.36 mmol) were combined in MeOH (5 ml), and the reaction was heated at 80° C. for 2 h. The reaction was diluted with EtOAc and washed with water. The aqueous portion was extracted with EtOAc, and the combined organic portions were dried (sodium sulfate), filtered and concentrated to give a pale yellow solid. The crude material was purified by preparatory HPLC, using a gradient of 35-75% acetonitrile/water (0.1% TFA) to give 53 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([CH3:13])[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:10]2[CH2:11][CH:12]([CH3:13])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9]2)=[O:23])=[CH:17][CH:16]=1
Reactant: CC1CNN=C1c1ccc(Cl)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: CC1CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
In a 500 ml round bottomed flask was placed 82 g (0.42 mole) of 3-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole dissolved in 300 ml of methylene chloride and the solution was brought to boiling. A solution of 64.5 g of 4-chlorophenyl isocyanate (0.42 mole) in 100 ml of methylene chloride was added at a rate to maintain reflux. After stirring for an additional 30 minutes the solvent was removed in vacuo and the resulting oil was crystallized from ethyl ether yielding 140 g of N,3-bis-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide. mp 139°-140° C. NMR data was consistent with the structure.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].[CH2:9](O)[C:10]1[O:14]C=[CH:12][CH:11]=1.Cl.[C:17]([O-:20])(O)=[O:18].[Na+]>>[C:17]([O:20][O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:18])[CH2:12][CH2:11][C:10]([CH3:9])=[O:14]
Reactant: OCc1ccco1
Reactant: O=C([O-])O
Reactant: CCCCOCCO
Agent: Cl
Agent: [Na+]
Product: CCCCOCCOOC(=O)CCC(C)=O

Procedure:
2-Butoxyethanol (Butyl Cellosolve) 47.2g (0.4 mol) and 157g (1.6 mol) furfuryl alcohol were added to 422g (3.9 mol) 2-butoxyethanol and 7.2g conc. HCl over 11/2 hours at 109°-114° and held at 108° for an additional 11/2 hours. Reaction product was neutralized with sat. NaHCO3, washed with water, dried with anhy. MgSO4 and distilled. 2-Butoxyethyl levulinate was collected in fr 2 95°-106° 1 mm, 95% ester by gc.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([OH:16])(=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>>[Cl:1][S:2]([C:12]1[CH:13]=[CH:14][C:9]([CH:8]=[CH:7][C:6]([OH:16])=[O:15])=[CH:10][CH:11]=1)(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)C=Cc1ccccc1
Agent: Cl
Product: O=C(O)C=Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 41 °C
Reaction time: 2 h
Yield: 20.3 %

Procedure:
To neat chlorosulfonic acid (5.3 ml, 80 mmol) at 0-5° C. temperature slowly cinnamic acid (41) (1.47 g, 10 mmol) was added. As the reaction proceeded hydrogen chloride gas evolved. The reaction mixture was stirred successively at 0° C. for 1 hour, at ambient temperature for 2 hours and at 40-42° C. for 2 hours. The dark, viscous syrup was poured onto ice, the precipitated solid was filtered and washed with water. The title compound (0.5 g, 20%) as a white solid was obtained. 1H NMR (DMSO-d6, HMDSO), δ: 6.55 (1H, d, J=16 Hz); 7.58 (1H, d, J=16.0 Hz); 7.65 (4H, s); 8.15 (1H, br s).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:9][C@H:8]1[C:10]1[N:15]=[C:14]2[N:16]([CH3:25])[C:17](=[O:24])[N:18]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]2=[CH:12][CH:11]=1)(=O)=O.[CH3:26][N:27]1[C:31](=[O:32])[CH2:30][NH:29][C:28]1=[O:33].[H-].[Na+]>CN(C=O)C>[CH3:22][C:20]([CH3:21])([CH3:23])[CH2:19][N:18]1[C:13]2[C:14](=[N:15][C:10]([C@@H:8]3[CH2:9][C@H:7]3[CH2:6][N:29]3[CH2:30][C:31](=[O:32])[N:27]([CH3:26])[C:28]3=[O:33])=[CH:11][CH:12]=2)[N:16]([CH3:25])[C:17]1=[O:24]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3COS(C)(=O)=O)nc21
Reactant: CN1C(=O)CNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CN(C[C@@H]2C[C@H]2c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
{(1R,2R)-2-[1-(2,2-Dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]cyclopropyl}methyl methanesulfonate (31-5, 68 mg, 0.18 mmol, 1.0 equiv) was added to anhydrous DMF (0.92 mL) and cooled to 0° C. 3-Methylimidazolidine-2,4-dione (31-6, 105 mg, 0.92 mmol, 5.0 equiv) and NaH (37 mg, 0.92 mmol, 5.0 equiv, 60% dispersion in oil) were added sequentially and the resulting mixture was warmed to RT. After 18 h, LCMS showed complete consumption of 31-5. Purification by reverse-phase HPLC (10-100% 0.1% TFA in H2O:CH3CN) afforded 31-7 as a colorless oil. MS m/z (M+H): calculated=332.1969; observed=332.1971.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1N.Cl.[N:11]([O-])=O.[Na+].[S:15](=[O:17])=[O:16]>C(O)(=O)C.O>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[S:15]([NH2:11])(=[O:17])=[O:16]
Reactant: O=S=O
Reactant: Cc1ccc(N)c(F)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(N)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Fluoro-4-methylaniline (3 g, 24 mmol) was dissolved in glacial acetic acid (45 ml) and concentrated hydrochloric acid (15 ml) and the solution was cooled to -10° C. with overhead stirring. Sodium nitrite (1.82 g, 26.4 mmol) in water (3 ml) was added dropwise over 0.5 h maintaining the temperature below -5° C. Stirring was continued for a further 0.5 h after the final addition. This mixture was added in small portions to a stirred, saturated solution of sulphur dioxide in acetic acid (30 ml) at 0° C. After addition the mixture was warmed to room temperature and stirred 1 h before pouring into iced water. After stirring for 0.5 h the product was extracted into ether and the aqueous layer further extracted with dichloromethane. The organic layers were combined, washed with brine, dried (MgSO4) and concentrated (azeotroping with toluene to remove any remaining acetic acid). A mixture of 1,4-dioxan (30 ml) and aqueous ammonia (30 ml of 0.88M) was added to the residue which was stirred overnight. The 1,4-dioxan was removed in vacuo and the aqueous layer extracted with ethyl acetate (2×100 ml). The organic layers were combined, washed with brine (100 ml), dried (MgSO4) and concentrated. Flash column chromatography (elution with 99% dichloromethane/1% methanol) gave the product as a pale yellow solid (1.62 g).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[NH2:40]/[C:41](/[CH3:47])=[CH:42]\[C:43]([O:45][CH3:46])=[O:44].[ClH:48]>C(O)(C)C>[ClH:48].[ClH:48].[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:42]([C:43]([O:45][CH3:46])=[O:44])=[C:41]([CH3:47])[NH:40][C:14]([CH3:16])=[C:13]3[C:12]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:23][CH2:22]3)=[O:17])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=Cc1cccc2nonc12
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)C1c1cccc2nonc12
Yield: 45 %

Procedure:
A mixture of 2,1,3-benzoxadiazole-4-carbaldehyde, 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate and methyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 and the product obtained was further treated with methanolic hydrogen chloride solution to give 2-(4-benzhydryl-1-piperazinyl)ethyl methyl 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride as light yellow crystals, m.p. 192°-198° C. Yield 45.0%.