Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5](=[O:10])[CH:6]([CH3:9])[CH:7]=[CH2:8].O.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>C(COC)OC>[CH3:9][C:6](=[C:5]1[O:10][CH2:2][CH2:3][O:4]1)[CH:7]=[CH2:8]
Reactant: C=CC(C)C(=O)OCCCl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: O
Solvent: COCCOC
Product: C=CC(C)=C1OCCO1
Temperature: 20 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
90.6 g (about 113 ml) of 20% potassium hydride in oil (density about 0.8) were washed twice with n-hexane under argon, and then treated with 700 ml of dimethoxyethane. Subsequently, a solution of 56.5 g (0.34 mol) of 2-methyl-but-3-enoic acid 2-chloroethyl ester with a content of 97.5% according to GC in 175 ml of dimethoxyethane was added thereto while stirring at 20° C. within 11/2 hours, and the mixture was stirred at room temperature for 1 hour. 250 ml of water were cautiously added dropwise thereto at 0°-5° C. The aqueous phase was then separated and extracted three times with three 300 ml portions, a total of 900 ml, of n-hexane. Washing of the combined organic phases with 250 ml of saturated sodium chloride solution, drying and concentration gave a yellow liquid (50.5 g; GC: 83.4%), which, after the addition of 40 mg of 2,6-di-tert.butyl-p-cresol, was fractionated on a Vigreux column (20 cm). This gave, at a boiling temperature of 93°-94° C./19 mbar, 28.22 g (66% yield) of 2-(1-methyl-allylidene)-[1,3]dioxolane as a colourless oil with a content of 100% according to GC.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[CH:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][C:18]=1[CH:27]([NH:34][C:9]([CH2:8][NH:7][C:6](=[O:12])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=1)=[O:11])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: NC(c1ccccc1)c1cc(C(F)(F)F)ccc1Cl
Agent: Cl
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1cc(C(F)(F)F)ccc1Cl

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(2-chloro-5-trifluoromethyl-phenyl)-C-phenyl-methylamine hydrochloride (CA [13954-13-7]).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>CO>[CH:20]1([NH:23][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)=[N:10][NH:11][CH:12]=3)[CH:5]=[CH:4][N:3]=2)[CH2:22][CH2:21]1
Reactant: NC1CC1
Reactant: Fc1ccc(-c2n[nH]cc2-c2ccnc(Cl)n2)cc1
Solvent: CO
Product: Fc1ccc(-c2n[nH]cc2-c2ccnc(NC3CC3)n2)cc1
Yield: 26 %

Procedure:
This compound was synthesized by stirring 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine prepared in accordance with Example A-299 with excess cyclopropylamine in methanol at 50° C. for 12 hours. The product, N-cyclopropyl-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinamine, was obtained as a white solid in 26% yield, mp: 203-204° C.; Anal. Calc'd for C16H14FN5: C, 65.07; H, 4.78; N, 23.71. Found: C, 64.42; H, 4.82; N, 23.58.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.CS(C)=O.[NH2:17][C:18]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][S:20][CH:19]=1>O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:17][C:18]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][S:20][CH:19]=1)=[O:4]
Reactant: CCOc1cscc1N
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cscc1NC(=O)c1ccccc1N

Procedure:
A mixture of 14.4 g. of isatoic anhydride, 22 ml. of dimethylsulfoxide and some ground glass is stirred and put in an oil bath at 120° C. A mixture of 12.6 g. of 3-amino-4-ethoxythiophene in 17 ml. of dimethylsulfoxide is added dropwise over 30 minutes at 120°-129° C. The mixture is heated at 125°-129° C. for one hour, cooled, poured into ice and water and extracted with dichloromethane. The extract is dried over magnesium sulfate, filtered and evaporated to an oil. This oil is dissolved in methanol, filtered, cooled and a few drops of water are added. The solid is removed by filtration and the filtrate is evaporated to an oil. This oil is dissolved in methanol, a few drops of water are added and the mixture is chilled overnight. The solid is collected by filtration giving o-amino-N-(4-ethoxy-3-thienyl)-benzamide.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: C1=COCCC1
Reactant: O=Cc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1ccccc1OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To salicylaldehyde (2.35 mL, 22.05 mmol) was added 45 mL methylene chloride, 3,4-dihydro-2H-pyran (5.0 mL, 54.8 mmol) and pyridinium p-toluenesulfonate (0.55 g, 2.19 mmol). The reaction mixture was allowed to stir at room temperature overnight. Additional pyridinium p-toluenesulfonate (0.55 g, 2.19 mmol) was added and the reaction mixture was stirred at room temperature for 4 days. The reaction mixture was poured into saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with two portions of methylene chloride. The combined organic layers were washed with saturated aqueous sodium chloride, dried (sodium sulfate), filtered, and concentrated to afford 2.96 g of an inseparable 60:40 mixture of salicylaldehyde and the title compound of Step A.
Reaction SMILES: O.[OH:2][C@@H:3]([CH2:18][OH:19])[CH2:4][O:5][CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:12](=[O:16])[NH:11][C:10]([NH2:17])=[N:9][C:8]1=2.[C:20](Cl)(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)C=O.N1C=CC=CC=1>[OH:2][C@H:3]([CH2:18][O:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][O:5][CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:12](=[O:16])[NH:11][C:10]([NH2:17])=[N:9][C:8]1=2
Reactant: Nc1nc2c(ncn2COC[C@@H](O)CO)c(=O)[nH]1
Reactant: CCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCC(=O)OC[C@@H](O)COCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C

Procedure:
A suspension of 410 mg (1.5 mmole) of (S)-9-(2,3-dihydroxy-1-propoxymethyl)guanine monohydrate in 6 ml of dry dimethylformamide and 1.5 ml of dry pyridine is stirred under a drying tube with cooling in an ice bath as a solution of 489 mg (3.0 mmole) of octanoyl chloride in 1.5 ml of dimethylformamide is added dropwise by syringe over approximately 5 minutes. The mixture is allowed to warm gradually to room temperature, and after 24 hours it is concentrated under high vacuum. The residual oil is purified by preparative TLC on nine 1000-μ silica gel plates (developed in 5:1 CHCl3 -MeOH). The product bands are isolated, combined, and extracted with dimethylformamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C:13]=3[CH:26]=2)[O:3]1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:27])[O:3][B:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]=[CH:14][C:13]=3[CH:26]=2)[O:5]1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)OB(c2ccc3c(c2)C=NCCO3)OC1(C)C
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethylethyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (3.0 g, 8.00 mmol) in dichloromethane (90 mL) and trifluoroacetic acid (10 mL) was heated to reflux for 1 h, and then cooled to room temperature. The reaction mixture was concentrated and the residue was azeotroped with toluene (100 mL) to give 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-benzoxazepine trifluoroacetate salt (2.9 g, quantitative yield). MS (EI) for C15H22BNO3: 276 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:18]2[C:9]3[NH:10][C:11](=[O:17])[C:12]4[N:13]([CH:14]=[CH:15][N:16]=4)[C:8]=3[C:7](=[CH:21][C:22]([OH:24])=[O:23])[C:6]=2[CH:5]=1)([O-])=O.[ClH:25]>>[ClH:25].[ClH:25].[NH2:1][C:4]1[CH:20]=[CH:19][C:18]2[C:9]3[NH:10][C:11](=[O:17])[C:12]4[N:13]([CH:14]=[CH:15][N:16]=4)[C:8]=3[C:7](=[CH:21][C:22]([OH:24])=[O:23])[C:6]=2[CH:5]=1
Reactant: O=C(O)C=c1c2cc([N+](=O)[O-])ccc2c2[nH]c(=O)c3nccn3c12
Agent: Cl
Product: Nc1ccc2c(c1)c(=CC(=O)O)c1c2[nH]c(=O)c2nccn21
Temperature: 40 °C

Procedure:
8-Amino-10-(carboxymethylene)-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one dihydrochloride may be obtained according to the following procedure: 35.5 g of 8-nitro-10-(carboxymethylene)-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one are added to 74.5 g of stannous chloride dihydrate in 550 ml of concentrated hydrochloric acid, followed by heating at 40° C. for 4 hours. After cooling to 25° C., the mixture is filtered and then washed with 3 times 200 ml of distilled water and twice 100 ml of acetone. The solid is dried at 60° C. under reduced pressure (1 mmHg; 0.13 kPa). 37.45 g of 8-amino-10-(carboxymethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one dihydrochloride are obtained in the form of a yellow solid, the melting point of which is greater than 260° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].[ClH:6].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[NH:25][CH2:24][CH2:23][C@@:20]4([C:21]=2[CH:22]=1)[C@@:15]3([O:28][CH3:29])[C@@H:16]([CH3:27])[CH2:17][C:18](=[O:26])[CH2:19]4.[CH:30]1([CH2:33]Br)[CH2:32][CH2:31]1>CN(C)C=O>[ClH:6].[CH:30]1([CH2:33][N:25]2[CH2:24][CH2:23][C@@:20]34[C:21]5[CH:22]=[C:9]([O:8][CH3:7])[CH:10]=[CH:11][C:12]=5[CH2:13][C@@H:14]2[C@:15]3([O:28][CH3:29])[C@@H:16]([CH3:27])[CH2:17][C:18](=[O:26])[CH2:19]4)[CH2:32][CH2:31]1
Reactant: BrCC1CC1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(OC)[C@@H](C)CC(=O)C3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@]1(OC)[C@@H](C)CC(=O)C3
Temperature: 100 °C

Procedure:
A slurry was made by the addition of sodium bicarbonate (1.24 g, 14.8 mol) to a solution of 3,14-dimethoxy-8β-methylmorphinan-6-one hydrochloride (37) (1.3 g, 3.7 mmol) and cyclopropylmethyl bromide (1 ml, 10.7 mmol) in 25 ml of dimethylformamide. This reaction mixture was heated at 100° C. under a nitrogen atmosphere, and after 16 hours the reaction mixture was cooled, sodium bicarbonate was removed by suction filtration and the filter cake washed thoroughly with dimethylformamide. After removal of the solvent by vacuum distallation (oil bath temperature 40°-45° C.), the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous phase was extracted with two additional portions of ethyl acetate. The organic fractions were combined, dried over Na2SO4 and concentrated under reduced pressure. Purification of the crude product by chromatography on Florisil (eluted with graded methanol/chloroform) yielded 1.0 g (75% theory) of the title compound as a golden oil. The hydrochloride salt of this compound was formed by taking up a sample of the oil in diethyl ether and adding ethereal hydrogen chloride to provide a colorless solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1([CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][C:26]=3[N:32]([CH3:41])[S:33]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)(=[O:35])=[O:34])=[O:22])[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>O>[CH2:1]([S:8][C:9]1([CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][C:26]=3[N:32]([CH3:41])[S:33]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)(=[O:35])=[O:34])=[O:22])[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1cccc2cc(C(=O)NCC3(SCc4ccccc4)CCC4(CC3)OCCO4)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CC(=O)O
Solvent: O
Product: CN(c1cccc2cc(C(=O)NCC3(SCc4ccccc4)CCC(=O)CC3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 70.4 %

Procedure:
A mixture of N-{[8-(benzylthio)-1,4-dioxaspiro[4.5]dec-8-yl]methyl}-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.21 g) and acetic acid (15 mL) was added at 80° C. for 24 hr, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (0.79 g, yield 71%) as a colorless amorphous solid from a fraction eluted with tetrahydrofuran-methanol (1:1, volume ratio). MS: 568(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:22][C:4]=1[CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39]([N:6]([CH2:5][C:4]1[CH:22]=[C:23]([C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[CH:24]=[CH:25][C:3]=1[O:2][CH3:1])[CH:7]1[CH2:8][CH2:9][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:12]1)=[O:40]
Reactant: COc1ccc(-c2ccc(C)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: COc1ccc(-c2ccc(C)nc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 68 (813 mg, 1.85 mmol) is treated with acid chloride 8 (542 mg, 2.03 mmol) using Method D to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].Br[CH2:11][CH2:12][O:13][CH2:14][CH2:15]Br.C([O-])([O-])=O.[K+].[K+].[I-].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[Cl:9]
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(N2CCOCC2)ccc1Br
Temperature: 80 °C
Reaction time: 48 h
Yield: 39.3 %

Procedure:
4-Bromo-3-chloroaniline (500 mg) was dissolved in DMF (10 ml), and bis(2-bromoethyl)ether (1.12 g), K2CO3 (1.34 g), and potassium iodide (80 mg) were added thereto, followed by stirring at 80° C. for 2 days. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0% to 20% EtOAc/hexane) to obtain 4-(4-bromo-3-chlorophenyl)morpholine (263 mg).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:16]=[C:11]3[C:10]([CH3:23])=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:23][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)[CH:16]=2)[NH:8][N:9]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(-c4cnn(C)c4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c2ncc(-c3cnn(C)c3)cc12
Temperature: 50 °C

Procedure:
To a solution of 1-(4-methoxybenzyl)-3-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridine (107) (60 mg, 0.179 mmol) dissolved in chloroform (10 mL) was added trifluoroacetic acid (5 mL) and the reaction mixture was heated at 50° C. for 12 h. After completion of the reaction the solvents were removed and diluted with cold water, pH was adjusted to 8 and the aqueous phase extracted with chloroform two times. The organic layer was washed with brine solution and dried over sodium sulphate and the solvents were removed. The crude was passed through 100-200 mesh silica gel eluting the compound at 80% ethyl acetate in hexane as pale yellow solid 3-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridine 108 (30 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[C:13]([N+:21]([O-])=O)[CH:12]=3)[N:10]=2)[CH:7]=1.CC(O)=O>[Fe].C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:18])[F:20])=[C:13]([NH2:21])[CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(-c2cn3cc(Cl)ccc3n2)ccc1C(F)(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2cn3cc(Cl)ccc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
Iron (0.140 g) is added to a mixture of 6-chloro-2-[3-nitro-4-(trifluoromethyl)phenyl]imidazo[1,2-a]pyridine (0.171 g), HOAc (0.230 mL) and EtOH—H2O (2 mL, 4:1). The mixture is stirred at 80° C. for 2 hours, then cooled, concentrated, taken into sat. NaHCO3 aqueous solution, extracted with EtOAc and CH2Cl2. Organics are dried and concentrated to give the title compound (150 mg, 96% yield), which is used without further purification. LCMS m/z=312.4 [M+H]+, tR=1.96 min.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].O.[CH:12]([NH2:14])=O>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([Cl:10])[CH:6]=2)[N:1]=[CH:12][N:14]=1
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: NC=O
Solvent: O
Product: Nc1ncnc2ccc(Cl)cc12
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 2-amino-5-chlorobenzonitrile (1.07 g, 7.0 mmol) in formamide (20 ml) was heated at 180° C. for 6 hours. After cooling to room temperature, water (30 ml) was added to the reaction mixture. The precipitate was collected by filtration, washed with water and dried over P2O5, yielding the title compound as a grey solid (1.2 g, yield: 95%) which was characterized by its mass spectrum as follows: MS (m/z): 180 ([M+H]+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]CCC(N)=O)=[C:10]([C:20]([F:23])([F:22])[F:21])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].[C:30]([C:32]1([NH:35][C:36]([C@H:38]2[N:42]([C:43]([C:45]3([C:48]([F:51])([F:50])[F:49])[CH2:47][CH2:46]3)=[O:44])[CH2:41][C@@H:40](OS(C3C=CC=CC=3)(=O)=O)[CH2:39]2)=[O:37])[CH2:34][CH2:33]1)#[N:31]>O1CCCC1.CN(C)C(=O)C.O>[C:30]([C:32]1([NH:35][C:36]([C@@H:38]2[CH2:39][C@@H:40]([S:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[CH:9][C:10]=3[C:20]([F:22])([F:21])[F:23])[CH2:41][N:42]2[C:43]([C:45]2([C:48]([F:51])([F:49])[F:50])[CH2:46][CH2:47]2)=[O:44])=[O:37])[CH2:33][CH2:34]1)#[N:31]
Reactant: Cc1cc(-c2ccc(SCCC(N)=O)c(C(F)(F)F)c2)ccn1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@H](OS(=O)(=O)c3ccccc3)CN2C(=O)C2(C(F)(F)F)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2ccc(S[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)N(C(=O)C4(C(F)(F)F)CC4)C3)c(C(F)(F)F)c2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.6 %

Procedure:
3-[4-(2-Methyl-pyridin-4-yl)-2-trifluoromethyl-phenylsulfanyl]-propionamide (200 g, 588 mmol) was dissolved in tetrahydrofuran (1.0 L) before sodium tert-butoxide (55.5 g, 578 mmol) was added and the fine suspension was stirred for 2 h at room temperature. N,N-dimethylacetamide (500 mL) was added and the solution was stirred for further 1.5 h. A solution of benzenesulfonic acid (3S,5S)-5-(1-cyano-cyclopropylcarbamoyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidin-3-yl ester (237.5 g, 504 mmol) in N,N-dimethylacetamide (500 mL) was added and the brown, clear solution was stirred for 40 h. The mixture was diluted with water (3 L) and extracted with tert-butyl methyl ether (1×2 L, 3×1 L). The combined organic extracts were washed with an aqueous sodium carbonate solution (1 M, 1.0 L) and brine (1.0 L), dried over sodium sulfate, and concentrated in vacuo to yield the title compound as a brown gum (327.8 g). The crude product (containing dimethylacetamide) was used in the next step without further purification. For characterization purposes, a 4 g sample of crude material was purified by filtration over silica gel (20 g, eluent: ethyl acetate (200 mL)). 3.3 g of purified material were obtained as an off-white solid. MS (EI): m/z=583.1 [M+H]+. 1H NMR (CDCl3, 300 MHz): δ 1.10-1.36 (m, 6H), 1.49-1.58 (m, 2H), 1.99-2.12 (m, 1H), 2.65 (s, 3H), 2.90-3.02 (m, 1H), 3.92 & 4.02 (ABX, JAB=11.9 Hz, JAX=4.8 Hz, JBX=5.8 Hz, each 1H), 4.12-4.22 (m, 1H), 4.71 (dd, J=4.7 Hz, 7.8 Hz, 1H), 7.31 (d, J=5.3 Hz, 1H), 7.37 (br s, 1H), 7.60-7.69 (m, 2H), 7.80 (d, J=8.3 Hz, 1H), 7.93 (s, 1H), 8.60 (d, J=5.1 Hz, 1H).
Reaction SMILES: CC(=O)CC(=O)CCCCC.C([N:19]1[CH:24]2[CH2:25][CH2:26][CH2:27][CH:20]1[C:21](=[O:40])[N:22]([C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1)[C:23]2=[O:28])C1C=CC=CC=1.C(OCC)(=O)C>[Pd].C(O)C>[F:39][C:36]([F:37])([F:38])[O:35][C:32]1[CH:33]=[CH:34][C:29]([N:22]2[C:23](=[O:28])[CH:24]3[NH:19][CH:20]([CH2:27][CH2:26][CH2:25]3)[C:21]2=[O:40])=[CH:30][CH:31]=1
Reactant: O=C1C2CCCC(C(=O)N1c1ccc(OC(F)(F)F)cc1)N2Cc1ccccc1
Agent: [Pd]
Agent: CCCCCC(=O)CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1C2CCCC(N2)C(=O)N1c1ccc(OC(F)(F)F)cc1
Reaction time: 2 h

Procedure:
3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo|3.3.1|nonane-2,4-dione: A mixture of 9-benzyl-3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione (120 mg, 0.3 mmol), 10% Pd/C (20 mg, 0.02 mmol Pd), ethyl acetate (8 mL), and ethanol (2 mL) were stirred vigorously under an atmosphere of H2. After 2 h, more ethanol (2 mL) was added. After an additional 16 h, the reaction was filtered through Celite and concentrated to give 3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione: MS (ESI): 315.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:20])[C:17](N)=[O:18])=[CH:15][C:9]=3[C:8](=[O:21])[CH2:7][C:6]=2[CH:22]=1.[OH-:23].[Na+].O.Cl>CCCCCC.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:20])[C:17]([OH:23])=[O:18])=[CH:15][C:9]=3[C:8](=[O:21])[CH2:7][C:6]=2[CH:22]=1
Reactant: [OH-]
Reactant: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1cc(Cl)ccc1S2
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CO
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1cc(Cl)ccc1S2
Temperature: 0 °C
Yield: 47.4 %

Procedure:
A mixture of 0.4 g of 2-(8-chloro-10,11-dihydro-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide, 6.0 g of sodium hydroxide, 50 ml of water and 60 ml of methanol was refluxed for 3 hours. The solvent was removed by distillation to obtain a residue, to which was added ice water, and the mixture was acidified with hydrochloric acid and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a residue, which was crystallized from benzene--n-hexane to give 190 mg (yield: 47%) of 2-(8-chloro-10,11-dihydro-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as a powder having a melting point of 195°-196° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH:13]C(=O)OCC2C=CC=CC=2)[CH2:8]1.CO.C(Cl)Cl>CO.[Pd]>[NH2:13][C@H:9]1[CH2:10][CH2:11][CH2:12][C@@H:7]([N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[CH2:8]1
Reactant: O=C(N[C@H]1CCC[C@@H](N2CCCC2=O)C1)OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: N[C@H]1CCC[C@@H](N2CCCC2=O)C1
Reaction time: 1.75 h

Procedure:
A degassed solution of benzyl (1S,3R)-3-(2-oxopyrrolidin-1-yl)cyclohexylcarbamate, 45b, (0.165 g, 0.522 mmol) and Pd on C (10% wet, Degussa, 0.050 g, 0.024 mmol) in MeOH (15 mL) was placed under H2 atm (balloon). After 105 min, TLC (10% MeOH-DCM) indicated complete consumption of starting material. H2 was removed and the solution filtered and concentrated in vacuo. The crude product was azeotroped with CH3CN (2×) to remove any residual MeOH and provided the desired product (96 mg): FIA (M+H+) 183.27