Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]#[N:24])=[CH:21][NH:20][N:19]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]#[N:24])=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Reactant: N#Cc1c[nH]nc1N
Product: Cc1ccc(-c2cc(C(F)(F)F)n3ncc(C#N)c3n2)cc1
Yield: 50 %

Procedure:
Reaction of 1-(4-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (230 mg, 1.0 mmol), prepared from commercially available 4-methyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (151 mg, 50%). MS (ISP) 303.1 [(M+H)+]; mp 121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][C:33]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:36](N)=[O:37])[CH2:32][CH2:31]3)[CH2:13][CH2:12][N:11](C(=O)C3C=C(OC)C(OC)=C(OC)C=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:45]1CCOCC1.Cl>O>[C:39]1([C:33]2([C:36]([OH:45])=[O:37])[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][C@:9]3([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH2:13][CH2:12][NH:11][CH2:10]3)[CH2:31][CH2:32]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Product: O=C(O)C1(c2ccccc2)CCN(CC[C@]2(c3ccc(Cl)c(Cl)c3)CCNC2)CC1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
Combine (+)-1-(2-(3-(3,4-dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-pyrrolidin-3-yl)-ethyl)-4-phenylpiperidine-4-carboxylic acid amide prepared by the method of U.S. Pat. No. 5,635,510, issued Jun. 3, 1997 (200 g, 300 mmol), dioxane (400 mL), concentrated aqueous hydrochloric acid (400 mL), and water (400 mL). Heat to reflux. After 26 hours, cool to ambient temperature and concentrate the reaction mixture in vacuo at about 60° C. to a volume of about 700 mL. Add water (400 mL) and extract with 9/1 ethyl acetate/hexaneo Separate the layers and extract the aqueous layer twice with 1/1 ethyl acetate/hexane. Adjust the pH of the aqueous layer to about 7 using sodium hydroxide to form a solid. Filter and dry to give (S)-3-(2-(4-phenyl-4-carboxypiperidin-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[CH:7]([CH2:13][NH:14][C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)[CH2:6]2.CO.[ClH:34]>O1CCCC1>[ClH:34].[ClH:34].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[CH:7]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:6]2
Reactant: COc1cc2c(cc1OC)C(CNC(=O)CCCCC(=O)NCCc1ccccc1)C2
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(cc1OC)C(CNCCCCCCNCCc1ccccc1)C2
Temperature: 25 °C

Procedure:
A 1 molar solution of borane-tetrahydrofuran complex (75.5 ml) was added to a solution of the product of step (a) (8.0 g) in tetrahydrofuran (160 ml) under an inert atmosphere. The solution was heated at reflux overnight, cooled to room temperature, and methanol (50 ml) cautiously added. When all effervescence had ceased, methanolic hydrogen chloride (50 ml) was added, and the mixture refluxed for an hour. The suspension was reduced to dryness giving a white solid which was crystallised from aqueous ethanol to give white needles, 6.88 g mp 258°-9°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[NH2:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:23]1[N:22]=[CH:21][N:20]=[C:19]([NH2:18])[CH:24]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccccc1-c1cc(N)ncn1
Yield: 58.3 %

Procedure:
To a solution of 2-methoxyphenyl boronic acid (X) (10.3 g, 68.2 mmol) in 300 ml of 1,4-dioxane was added 100 ml of saturated aqueous sodium carbonate solution. Argon gas was purged for 30 min at room temperature. Then 4-amino-6-chloropyrimidine (I) (8.8 g, 68.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.9 g, 3.4 mmol) were added simultaneously and argon gas was bubbled through the mixture for another 20 min. The reaction mixture was heated to reflux for 12 hours (TLC confirmed completion of the reaction) and was then concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate and concentrated. The obtained crude residue was purified by silica gel column chromatography eluting with 15% ethyl acetate in dichloromethane to provide 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine (XXIV) (8.0 g).
Reaction SMILES: NC1C=C(C2SC3C=CC=CC=3N=2)C([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=CC=1.[N:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][C:36]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:30][CH:29]=1)=[N+]=[N-]>>[NH2:25][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][C:36]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:30][C:29]=1[O:11][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:8]
Reactant: Cc1ccc2nc(-c3ccc(N=[N+]=[N-])cc3)sc2c1
Reactant: Nc1ccc(OS(=O)(=O)C(F)(F)F)c(-c2nc3ccccc3s2)c1
Product: Cc1ccc2nc(-c3ccc(N)c(OS(=O)(=O)C(F)(F)F)c3)sc2c1

Procedure:
This compound was prepared in a similar way to the compound of Example XIV from 2-(4-azidophenyl)-6-methyl-benzothiazole. (Found: M+ 388. C15H11F3N2O3S2 requires MW 386).
Reaction SMILES: Cl[Si:2]([CH3:16])([CH3:15])[Si:3]([CH:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([CH3:13])=[C:7]1[CH3:14])([CH3:5])[CH3:4].[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>CCOCC>[C:17]([NH:21][Si:2]([CH3:16])([CH3:15])[Si:3]([CH:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([CH3:13])=[C:7]1[CH3:14])([CH3:5])[CH3:4])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: CC1=C(C)C([Si](C)(C)[Si](C)(C)Cl)C(C)=C1C
Solvent: CCOCC
Product: CC1=C(C)C([Si](C)(C)[Si](C)(C)NC(C)(C)C)C(C)=C1C
Temperature: 25 °C

Procedure:
To a solution of 3.000 g (11.0 mmol) 1-chloro-2-(tetramethylcyclopentadienyl)-1,1,2,2-tetramethyldisilane in 50 mL ether was added 2.422 g (33.1 mmol) tert-butylamine. Precipitate formed rapidly. The slurry was stirred for several days at room temperature, then was gently heated to drive the reaction to completion. The solvent was removed, the residue was extracted with pentane, the amine hydrochloride was filtered and the pentane was removed under reduced pressure to give the product as a yellow oil. The yield was 3.150 (92.5%). Mass spec: m/e 309. 1H NMR (C6D6) δ 2.75 (s, 1H), 1.95 (s, 6H), 1.82 (s, 6H), 1.08 (s, 9H), 0.51 (s, 1H), 0.24 (s, 6H), 0.16 (s, 6H); 13C NMR (C6D6) δ 135.2, 134.4, 55.2, 50.3, 34.1, 14.9 11.6, 3.3, −1.4.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([C@H:25]([NH2:29])[C:26]([OH:28])=[O:27])[CH2:11][C:12]([NH:14][C@H:15]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:16][SH:17])=[O:13]>CC(C)=O.O>[NH2:29][C@H:25]([C:26]([OH:28])=[O:27])[CH2:10][CH2:11][C:12]([NH:14][C@H:15]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:16][S:17][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Solvent: O
Solvent: CC(C)=O
Product: N[C@@H](CCC(=O)N[C@@H](CSC(=O)c1ccccc1)C(=O)NCC(=O)O)C(=O)O
Temperature: 25 °C
Yield: 78 %

Procedure:
Using in the procedure of Example 1 benzoyl chloride in place of pivaloyl chloride, L-glutathione reduced (15.4 g) affords a crude white solid which is suspended in boiling acetone/water (3/1; 400 ml) for thirty minutes. After cooling at room temperature the white precipitate is collected by filtration and washed with acetone (20 ml). Under vacuum drying yields γ-L-glutamyl-S-benzoyl-L-cysteinyl-glycine (16 g yield=78%).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2.[CH3:14]I>C1COCC1>[CH3:14][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: Oc1cccc2cccnc12
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc2cccnc12
Yield: 102.4 %

Procedure:
Add potassium hydroxide (435 g, 7.76 mol) to a solution of 8-hydroxy quinoline (250 g, 1.724 mol) in THF (10 L) at ambient temperature and stir. Add methyl iodide (435 g, 2.58 mol) dropwise and stir overnight. Filter the reaction mixture and wash the solid with THF (2 L). Concentrate the solution to dryness; add water; extract with dichloromethane (2×3 L); combine the organic layers; and wash with brine. Collect the organic layers and dry over sodium sulfate. Remove the solids by filtration. Collect the filtrate and concentrate under reduced pressure to give a red oil, which solidifies on standing, to give the title compound (281 g, 102%), which can be used without further purification. ESI (m/z) 160(M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)=[O:4].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1c[nH]cn1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cn(-c2cccc([N+](=O)[O-])c2)cn1
Temperature: 150 °C
Yield: 66.6 %

Procedure:
1H-Imidazole-4-carboxylic acid methyl ester (1 g, 7.9 mmol) was dissolved in MeOH and NaH (348 mg, 8.7 mmol) was added slowly. When the gas evolution had ceased 1-fluoro-3-nitro benzene (926 uL, 8.7 mmol) was added, and the mixture was heated to 150° C. under N2 for 16 h. After cooling to room temperature the precipitation was isolated by suction filtration, washed with MeOH, and dried under vacuum to afford 1.3 g (67%) of 20. HRMS (ESI+): m/z=247.2091 [M+H]
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=2)=[CH:12][CH:11]=1.[C:25](Cl)(Cl)=[S:26]>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]3[NH:23][C:25](=[S:26])[NH:24][C:19]=3[CH:18]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(Cc2ccc(N)c(N)c2)cc1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cc2ccc3[nH]c(=S)[nH]c3c2)cc1

Procedure:
To a solution of 0.51 g (5.0 mmoles) of triethyl amine, 1.14 g (5.0 mmoles) of 4-[(4-methoxyphenyl)-methyl]-o-phenylene-diamine and 35 ml of chloroform a solution of 0.58 g (5.0 mmoles) of thiophosgene and 10 ml of chloroform are added dropwise.
Reaction SMILES: C([BH3-])#N.[Na+].[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([CH3:15])[NH:10]2.N>C(O)(=O)C>[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]([CH3:15])[NH:10]2
Reactant: Cc1cc2c(Br)cccc2[nH]1
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1Cc2c(Br)cccc2N1
Temperature: 14 °C
Reaction time: 0.25 h

Procedure:
7.99 g of sodium cyanoborohydride are gradually added to a solution of 8.90 g of 4-bromo-2-methylindole (which can be prepared according to patent US2010/160647 A1, 2010) in 310 ml of acetic acid under argon cooled to a temperature of about 14° C. The reaction mixture is stirred at a temperature of about 14° C. for 15 minutes, and it is then allowed to warm up to ambient temperature. After 2 hours, the reaction mixture is poured into an Erlenmeyer flask containing ice-cold water (200 ml) and then the pH is brought to 9 with an aqueous ammonia solution. The reaction medium is extracted with dichloromethane (2×200 ml) and then the organic phases are combined, washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. After purification of the residue by silica column chromatography, elution being carried out with a mixture of heptane and ethyl acetate (90/10), 5.92 g of 4-bromo-2-methylindoline are obtained, the characteristics of which are the following:
Reaction SMILES: N[C@@H]1[C:8](=[O:9])[N:7]2[C@@H]1S[C@](C(O)=O)(N1CCN(N=CC3C=CC(C)=CC=3)C1=O)C2.[NH2:28][C@@H:29]1[C:35](=[O:36])[N:34]2[C@@H:30]1[S:31][C@@:32]([N:40]1[CH2:44][CH2:43][N:42]([N:45]=CC3C=CC=C(OC)C=3)[C:41]1=[O:55])([C:37]([OH:39])=[O:38])[CH2:33]2>>[NH2:28][C@@H:29]1[C:35](=[O:36])[N:34]2[C@@H:30]1[S:31][C@:32]([C:37]([OH:39])=[O:38])([N:40]1[CH2:44][CH2:43][N:42]([NH:45][C:8]([NH2:7])=[O:9])[C:41]1=[O:55])[CH2:33]2
Reactant: Cc1ccc(C=NN2CCN([C@]3(C(=O)O)CN4C(=O)[C@@H](N)[C@H]4S3)C2=O)cc1
Reactant: COc1cccc(C=NN2CCN([C@]3(C(=O)O)CN4C(=O)[C@@H](N)[C@H]4S3)C2=O)c1
Product: NC(=O)NN1CCN([C@]2(C(=O)O)CN3C(=O)[C@@H](N)[C@H]3S2)C1=O

Procedure:
(3R,5R,6R)-6-amino-3-carboxy-3-[3-(p-methylbenzylideneamino)-2-oxoimidazolidin-1-yl-]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane and (3R,5R,6R)-6-amino-3-(3-anisylideneamino-2-oxoimidazolidin-1-yl)-3-carboxy-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane were treated in the same manner to obtain (3R,5R,6R)-6-amino-3-carboxy-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane. The physical property (IR) of this product were identical with that obtained above.
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[C:12]([F:20])[CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[O:28][CH:29]=2)[N:3]=1.N(OCCC(C)C)=O.[Cl-:45].[NH4+]>C(#N)C.[Cu](Cl)Cl>[Cl:45][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[C:12]([F:20])[CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)[O:28][CH:29]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)c(F)c1
Reactant: [Cl-]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Agent: [NH4+]
Solvent: CC#N
Product: N#Cc1c(Cl)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.287 mmol) of 2-amino-6-({[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl}sulfanyl)-4-[3-fluoro-4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile (Example 20) are initially charged in 20 ml of acetonitrile, 258 μl (1.724 mmol) of isoamyl nitrite and 232 mg (1.724 mmol) of copper(II) chloride are added and the mixture is stirred at room temperature overnight. The reaction mixture is then added to saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue is purified by preparative HPLC (mobile phase gradient: acetonitrile/water 10:90→95:5). This gives 25 mg (16% of theory) of the target compound.
Reaction SMILES: I[CH2:2][C:3]1([CH3:13])[O:8][CH2:7][C@@H:6]2[CH2:9][NH:10][CH2:11][CH2:12][N:5]2[CH2:4]1.CCN(CC)CC>CO.[Pd]>[CH3:2][C:3]1([CH3:13])[O:8][CH2:7][C@@H:6]2[CH2:9][NH:10][CH2:11][CH2:12][N:5]2[CH2:4]1
Reactant: CC1(CI)CN2CCNC[C@H]2CO1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1(C)CN2CCNC[C@H]2CO1
Yield: 65.6 %

Procedure:
(9aS)-3-(iodomethyl)-3-methyloctahydropyrazino[2,1-c][1,4]oxazine (53 mg, 0.179 mmol) was dissolved in MeOH (5 ml) and Et3N (0.037 mL, 0.268 mmol) was added. The flask was purged with Ar, and Pd/C (19.05 mg, 0.018 mmol) was added. A balloon with H2 was attached and the flask was evacuated and filled with H2 3×. The reaction was stirred over the weekend. The reaction mixture was filtered through celite, rinsing with MeOH. The solvent was removed in vacuo to give (S)-3,3-dimethyloctahydropyrazino[2,1-c][1,4]oxazine (20 mg) as a yellow solid. The crude material was taken onto the next step.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[F:35])=[O:25])[C:21](O)=[O:22]>>[F:35][C:29]1[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=1[CH2:27][NH:26][C:24](=[O:25])[CH:20]([CH3:19])[C:21]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)ccc1F
Product: CC(C(=O)NCc1cc(F)ccc1F)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=464.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(2,5-difluoro-benzyl)-malonamic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:17][C:9]2[CH:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:27]1[N:32]=[N:31][C:30]([C:33]([OH:35])=O)=[CH:29][CH:28]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].[CH2:36]([NH2:42])[C:37]1[O:41][CH:40]=[CH:39][CH:38]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:18]2[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([C:27]3[N:32]=[N:31][C:30]([C:33]([NH:42][CH2:36][C:37]4[O:41][CH:40]=[CH:39][CH:38]=4)=[O:35])=[CH:29][CH:28]=3)[C:8]3[C:15](=[O:16])[N:14]4[CH:10]([CH2:11][CH2:12][CH2:13]4)[C:9]=3[N:17]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1c(Cc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)O)nn1)C(=O)N1CCCC21
Reactant: NCc1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(Cc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)NCc3ccco3)nn1)C(=O)N1CCCC21
Reaction time: 2 h

Procedure:
The mixture of 6-[3-(ethoxycarbonyl)-2-(4-fluorobenzyl)-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl]-3-pyridazinecarboxylic acid (G, 33 mg, 0.07 mmol), furfurylamine (19.3 mmol, 0.14 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.7 mg, 0.14 mmol) and 1-hydroxybenzotriazole hydrate (18.8 mg, 0.14 mmol) in 2 ml dichloromethane was stirred for 2 hours. The mixture was then partitioned between water and ethyl acetate. The organic was washed with brine and dried over sodium sulfate. The residue upon the removal of the solvent was purified with flash chromatography. Twelve (12) mg white solid was obtained. NMR (400 MHz, CDCl3) δ 8.38 (d, 1H), 8.08 (d, 1H), 7.20 (t, 2H), 6.92 (t, 2H), 4.78 (m, 1H), 4.67 (d, 2H), 4.40 (dd, 2H), 3.90 (q, 2H), 3.64 (m, 1H), 3.39 (m, 1H), 2.48 (m, 1H), 2.35 (m, 2H), 1.40 (m, 1H), 0.90 (t, 3H) ppm. ESI-MS m/z 556 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:21]=[CH:20][C:8]2[N:9]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[NH:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CO>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:10]1[NH:11][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:21]=[CH:20][C:8]=2[N:9]=1
Reactant: COC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reaction time: 24 h

Procedure:
Take 2-(2,6-Dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid methyl ester (1.00 g, 3.11 mmol) up in MeOH (6 mL) and 1 N NaOH (6 mL) and stir for 24 hr. Add additional 1 N NaOH (6 mL) and stir for an additional 30 hr. Concentrate under reduced pressure. Neutralize the concentrate at 0° C. by the dropwise addition of 1 N HCl (12 mL). Collect the resulting precipitate and wash with water followed by Et2O. Dry the solid in a vac oven to afford the desired acid as a tan solid: 1H NMR (400 MHz, DMSO-d6) ppm 7.60-7.67 (m, 1 H) 7.68 (s, 2 H) 7.70 (d, J=2.15 Hz, 1 H) 7.89 (d, J=8.46 Hz, 1H) 8.24 (br. s., 1 H) 12.83 (br. s., 1 H) 13.23 (br. s., 1 H); (M+H)+306.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][C:23]2[CH:24]=[C:25]([NH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:26]=[C:27]([CH3:29])[CH:28]=2)=[CH:16][CH:15]=1)#[N:13].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:30]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:25]1[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([O:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)[CH:24]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCOC(=O)CNc1cc(C)cc(OCCc2ccc(C#N)cc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)CN(c1cc(C)cc(OCCc2ccc(C#N)cc2)c1)S(=O)(=O)c1ccccc1Cl
Reaction time: 2 h
Yield: 62 %

Procedure:
2-Chlorobenzenesulfonyl chloride (0.225 g; 1.06 mmol) was added to a cold solution (ice:water temperature) of 3-[2-(4-cyanophenyl)ethoxy]-5-methylphenylaminoacetic acid, ethyl ester (0.30 g; 0.88 mmol; from step (i) above) in pyridine (10 mL). After 2 hours stirring the temperature was allowed to rise to ambient. After 4 hours at this temperature more 2-chlorobenzenesulfonyl chloride (0.056 g; 0.26 mmol) was added and the mixture was left overnight. The mixture was then poured into aqueous saturated NaHCO3 and extracted twice with Et2O. The combined ether phases where washed with HCl/aq (2M), H2O and brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (SiO2; EtOAc:heptane (1:3)) to give 0.28 g (62%) of the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][NH2:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:19][C:20]1[CH:21]=[C:22]([NH:28][C:29](=O)[O:30]C2C=CC=CC=2)[CH:23]=[CH:24][C:25]=1[CH2:26][OH:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][NH:14][C:29]([NH:28][C:22]3[CH:23]=[CH:24][C:25]([CH2:26][OH:27])=[C:20]([F:19])[CH:21]=3)=[O:30])=[CH:11][C:10]([C:15]([F:16])([F:17])[F:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(CO)c(F)c1)Oc1ccccc1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(CO)c(F)c1
Reaction time: 16 h
Yield: 57.2 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (100 mg, 0.316 mmol, 1.0 eq.) in DCM (2.0 mL) was added TEA (0.07 mL, 0.632 mmol, 3.0 eq) followed by phenyl 3-fluoro-4-(hydroxymethyl)phenylcarbamate (82.4 mg, 0.316 mmol, 1.0 eq.) at RT and stirred for 16 h. After completion of the reaction, a solid precipitate was filtered and washed with DCM (2 mL) followed by n-pentane (5 mL) and dried to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(hydroxymethyl)phenyl)urea (compound A59) (80 mg; 47%, white solid; TLC system: EtOAc/PE (3:2); Rf: 0.2).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[CH:13][C:12]=2[C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([Si](C)(C)C)=[CH:20][C:19]=1[F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:29]Cl>C(Cl)Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>[C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[CH:13][C:12]=2[C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:29])=[CH:20][C:19]=1[F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc2sncc2c1Nc1ccc([Si](C)(C)C)cc1F
Reactant: ClI
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc2sncc2c1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution 4-(2-fluoro-4-trimethylsilanyl-phenylamino)-benzo[d]isothiazole-5-carboxylic acid tert-butyl ester (416 mg, 1.0 mmol) in DCM (10 mL) at −78° C. was added iodine monochloride as a solution in DCM (2.0 mL, 1M, 2.0 mmol). The reaction mixture was stirred at −78° C. for 1 hour then diluted with saturated aqueous sodium thiosulfate solution and extracted with DCM. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to yield the title compound as a yellow foam (459 mg, 98%). LCMS (Method B): RT=5.32 min, [M+H]+=471.