Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:14][CH3:15])[CH2:12][CH3:13])(=[O:10])=[O:9])=[C:6]([OH:16])[C:5]([NH:17][C:18]2[C:21](=O)[C:20](=[O:23])[C:19]=2[O:24]CC)=[CH:4][CH:3]=1.[NH2:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30]>C1COCC1>[Cl:1][C:2]1[C:7]([S:8]([N:11]([CH2:12][CH3:13])[O:14][CH3:15])(=[O:9])=[O:10])=[C:6]([OH:16])[C:5]([NH:17][C:18]2[C:19](=[O:24])[C:20](=[O:23])[C:21]=2[NH:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:4][CH:3]=1
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(CC)OC)c2O)c(=O)c1=O
Reactant: CCC(N)CC
Solvent: C1CCOC1
Product: CCC(CC)Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(CC)OC)c2O)c(=O)c1=O
Temperature: 50 °C

Procedure:
To a stirred solution of 6-Chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide (Intermediate FA) (100 mg, 0.25 mmol) in THF (2 ml) was added 3-aminopentane (29 mg, 0.25 mmol) The reaction mixture was heated at 50° C. overnight. Further 3-aminopentane (29 mg, 0.25 mmol) was added and the reaction was heated at 50° C. for 7 hours. The reaction mixture was concentrated in vacuo and dissolved in EtOAc. The EtOAc solution was washed with 10% citric acid (aq), brine, dried (sodium sulfate) and concentrated in vacuo to give a solid; [M+H]+ 446.1. 1H NMR (DMSO) 0.9 (6H, t, 2×CH3), 1.2 (3H, t, CH3), 1.5 (2H, m), 1.6 (2H, m), 3.3 (2H, m), 3.7 (3H, s, CH3) 3.9 (1H, m), 7.2 (1H, d), 8.1 (1H, d), 8.3 (1H, d), 9.4 (1H, s), 10.2 (1H, s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:7]([CH:9]=[O:10])=O.[OH2:11].[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O>[N:1]1([C:9]([OH:10])([OH:11])[CH2:7][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O
Reactant: C1CNCCN1
Reactant: O=CC=O
Product: OC(O)(CN1CCNCC1)N1CCNCC1
Temperature: 35 °C

Procedure:
To a two liter kettle equipped with a reflux condenser, addition flask, immersion thermometer, mechanical stirrer and nitrogen purge system was added 515.8 g (6 moles) piperazine dissolved in 600 ml water. The contents in the resin kettle were stirred under nitrogen at 35° C. 218 g of 40 wt % glyoxal (1.5 moles) in water were diluted further with 70 g of water and added dropwise to the reactor contents over a period of twenty minutes. The reactor contents were allowed to stir at ambient temperature for thirty minutes. The reactor mixture became yellow and cloudy. A white crystalline solid was deposited on the kettle walls. The white crystalline solid was identified as piperazine hydrate by infrared spectrometry. The reactor mixture was filtered using a sintered funnel of medium porosity by vacuum. A tan colored solid was recovered. On washing with ethanol, the tan colored solid became a white solid. Infrared spectroscopy of the white solid showed no evidence of carbonyl groups but the presence of hydroxyl groups. Electron impact and chemical ionization mass spectrometry indicated the white solid was 1,2-bis (piperazinyl) ethanediol: ##STR4## The white solid was found to contain 56.3% carbon, 8.88% hydrogen, 22.1% nitrogen and 12.72% oxygen by CHN analysis. The percent carbon, hydrogen, nitrogen and oxygen calculated from the molecular formula of 1,2-bis (piperazinyl) ethanediol is 52.2, 9.6, 24.3 and 13.9%, respectively. The percent yield for 1,2-bis (piperazinyl) ethanediol was 23.3%. The filtrate was transferred to a liter round bottom flask and water removed by rotary evaporation. A brown oily water soluble liquid remained after the rotary evaporation. Infrared spectroscopy showed the brown oil liquid consisted of piperazine hydrate, a compound containing an amide group (1645 cm-1) and 1,2-bis(piperazinyl)ethanediol. Electron impact ionization mass spectroscopy indicated the compound containing the amide group was 2-hydroxy-1-(1-piperazinyl) ethanone: ##STR5##
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[N:4]1)[CH3:2].[B-](F)(F)(F)[F:14].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(#N)C>C(O)(=O)C>[CH2:1]([N:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:14])[CH:5]=[N:4]1)[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)c1ccnn1CC
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)c1c(F)cnn1CC
Temperature: 100 °C

Procedure:
A microwave vial was charged with ethyl 1-ethyl-1H-pyrazole-5-carboxylate (0.2 g) and Selectfluor™ (0.548 g) followed by acetonitrile (3 ml) and acetic acid (0.5 ml). The mixture was heated at 100° C. under microwave irradiation for 120 min. Selectfluor™ (0.548 g) was added and the mixture was heated was heated at 100° C. under microwave irradiation for 60 min. The solvent was removed in vacuo and the residue was partitioned between DCM (15 ml) and water (15 ml) and separated by hydrophobic frit. The aqueous layer was washed with dichloromethane (2×5 ml) and the combined organic layers concentrated in vacuo. Purification by chromatography on silica gel (20 g silica cartridge) eluting with a gradient of 0-50% DCM in cyclohexane over 20 min gave the title compound (67 mg) as a colourless oil.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10]/[C:11](=[CH:12]/[CH:13]=[CH:14]/[CH:15]=[O:16])/[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17]([O:23][CH3:24])(=[O:22])[CH2:18][C:19]([CH3:21])=[O:20]>>[CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10]/[C:11](=[CH:12]/[CH:13]=[CH:14]/[CH:15]([OH:16])[CH2:21][C:19](=[O:20])[CH2:18][C:17]([O:23][CH3:24])=[O:22])/[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C/C=C/C=C1/CCCCc2ccccc21
Reactant: COC(=O)CC(C)=O
Product: COC(=O)CC(=O)CC(O)/C=C/C=C1/CCCCc2ccccc21

Procedure:
By the method of Example 1, (2E,4Z)-4-(8,9-dihydro-6H,7H-benzocyclohepten-5-ylidene)-2-butenal (2.6 g, 12 mmol) was reacted with methyl acetoacetate to form title product, 3.2 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:11]=[N:10]1.C([O-])([O-])=O.[K+].[K+].[CH:26]1[CH:31]=[CH:30][C:29]([CH2:32][O:33][C:34](Cl)=[O:35])=[CH:28][CH:27]=1.O>ClCCl>[CH2:32]([O:33][C:34]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:11]=[N:10]2)=[C:2]([F:1])[CH:7]=1)=[O:35])[C:29]1[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(-n2cc(-c3ccccn3)cn2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(-n2cc(-c3ccccn3)cn2)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
200 mg of 2-(1-(2-fluoro-4-aminophenyl)-1H-pyrazol-4-yl)pyridine (25f) was dissolved in 5 mL dichloromethane, with addition of 194.3 mg K2CO3. Then, 990 μL Cbz-Cl was slowly dropped into the resultant mixture maintained in an ice bath. After completion of the addition, the ice bath was removed. The reaction mixture was warmed naturally to room temperature and reacted for 2 hours. TLC monitoring was performed to determine the completion of the reaction, after which water was added into the reaction solution. The mixture was extracted with dichloromethane for three times. The combined organic phase was dried and rotary evaporated. The residue obtained was repeatedly washed with petroleum ether until the excess Cbz-Cl was completely removed, thereby affording 260 mg of a light yellow solid, with a yield of 95.1%.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:12]1[CH:13]=[C:14]([C:23](=[O:25])[CH3:24])[CH:15]=[C:16]([N:20]([CH3:22])[CH3:21])[C:17]=1[O:18][CH3:19])([CH3:11])([CH3:10])[CH3:9].[Br:26]N1C(=O)CCC1=O.C(OCC)(=O)C>O1CCCC1>[Br:26][CH2:24][C:23]([C:14]1[CH:15]=[C:16]([N:20]([CH3:22])[CH3:21])[C:17]([O:18][CH3:19])=[C:12]([C:8]([CH3:11])([CH3:9])[CH3:10])[CH:13]=1)=[O:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(N(C)C)cc(C(C)=O)cc1C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(N(C)C)cc(C(=O)CBr)cc1C(C)(C)C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
Triethylamine (3.2 ml, 22.9 mmol) and tert-butyl dimethylsilyltrifluoromethanesulfonate (3.02 g, 11.4 mmol) were added to a solution of 1-[3-(tert-butyl)-5-(dimethylamino)-4-methoxyphenyl]-1-ethanone (1.9 g, 7.63 mmol) in tetrahydrofuran (50 ml) while cooling on ice and the mixture was stirred at the same temperature for 30 minutes, after which N-bromosuccinimide (2.7 g, 15.2 mmol) was added and stirring was continued for 30 minutes. Ethyl acetate was added, the reaction mixture was washed with brine and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and then the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (2.2 g) as a white solid.
Reaction SMILES: [C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:19](OCC)=[O:20]>>[CH:19]([NH:16][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)=[CH:18][CH:17]=1)=[O:20]
Reactant: CCOC=O
Reactant: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Product: O=CNc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1

Procedure:
A suspension of 10.0 g. (0.041 mole) of p-(1-adamantyloxy)aniline in 60 ml. ethyl formate was stirred at reflux for 48 hours. The mixture was then taken to dryness and the residue recrystallized from Me2CO:cyclohexane. There was obtained 9.67 g. (87%) of the amide, N-formyl-p- (1-adamentyloxy)aniline m.p. 149°-150°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:16](=O)[CH3:17])[CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7](=O)[CH3:8])C.O.[NH2:21][NH2:22]>C(O)C>[CH3:1][O:3][C:4]([C:5]1[CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH3:8])=[N:21][NH:22][C:16]=1[CH3:17])=[O:19]
Reactant: CCOC(=O)C(C(C)=O)C(C(C)=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COC(=O)C1=C(C)NN=C(C)C1c1ccccc1

Procedure:
19 g (75 mmols) of 2-acetyl-4-oxo-3-phenyl-pentanoic acid ethyl ester were heated to the boil together with 3.75 g (75 mmols) of hydrazine hydrate in 100 ml of ethanol under nitrogen for 10 hours. The solvent was then distilled off in vacuo and the residue was recrystallised from isopropanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])=[N:8][CH:9]=1)([O-])=O>CO.C1COCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])=[N:8][CH:9]=1
Reactant: O=C1CCCCN1c1ccc([N+](=O)[O-])cn1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(N2CCCCC2=O)nc1
Yield: 48.3 %

Procedure:
5′-Nitro-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one (0.66 g, 2.98 mmol) was dissolved in 1:1 MeOH/THF (50 mL) and hydrogenated over RaNi (1 g) at 4285 psi/mole for 0.8 h. The catalyst was filtered, and the filtrate concentrated. The crude solid was purified by recrystalization from THF and hexanes to give the product as a yellow solid (0.275 g, 48%). MS: APCI (AP+): 192.1 (M)+.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CC#N>[Br-:22].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: CCCCCCCCCBr
Solvent: CC#N
Product: CCCCCCCCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)C2
Product: [Br-]
Yield: 61.7 %

Procedure:
Following the general procedure outlined in Example 2, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (29.3 mg, 0.105 mmol) and 1-bromononane (0.04 mL, 0.2 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) were reacted to give the desired product (31.5 mg, 62%). EI-MS m/z 407 (M+) Rt (2.23 min).
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[C:10]([N+:14]([O-])=O)[C:11]([F:13])=[CH:12][C:7]=2[S:6][C:5]1=[O:17])[CH:2]=[CH2:3].O>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:14][C:10]1[C:11]([F:13])=[CH:12][C:7]2[S:6][C:5](=[O:17])[N:4]([CH2:1][CH:2]=[CH2:3])[C:8]=2[CH:9]=1
Reactant: C=CCn1c(=O)sc2cc(F)c([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: C=CCn1c(=O)sc2cc(F)c(N)cc21
Temperature: 80 °C
Yield: 97.2 %

Procedure:
A suspension of iron powder (0.77 g) in 5% aqueous acetic acid (1.5 ml) was heated at 80° C., and a solution of 3-allyl-6-fluoro-5-nitro-2(3H)-benzothiazolone (0.70 g) in acetic acid (2.8 ml) and ethyl acetate (2.8 ml) was added thereto, followed by heating under reflux at 60° to 80° C. for 3 hours. After cooling, water and ethyl acetate were added to the resultant mixture, followed by filtration. The filtrate was extracted with ethyl acetate, and the extract was washed with water and sodium bicarbonate solution, dried and concentrated to give 5-amino-3-allyl-6-fluoro-2(3H)-benzothiazolone (0.60 g). nD26.0 1.6236.
Reaction SMILES: [CH3:1][C:2](O)([C@@H:4](/[CH:6]=[CH:7]/[C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:30])[CH2:20][C@@H:21]2O)=[CH:16][CH:15]=3)[CH2:12][CH2:11]1)[CH3:9])C)[CH3:3].[N+]([O-])([O-])=O.[K+]>CCOCC.O1CCCC1>[CH3:23][C:22]1[CH2:21][CH2:20][C@H:19]([OH:30])[CH2:18][C:17]=1/[CH:16]=[CH:15]\[C:14]1[C@@H:13]2[CH2:12][CH2:11][C@H:10]([C@@H:8]([CH2:7][CH2:6][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:9])[C@@:27]2([CH3:28])[CH2:26][CH2:25][CH:24]=1
Reactant: C[C@H](/C=C/[C@@H](C)C(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1=C(/C=C\C2=CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]23)C[C@@H](O)CC1
Yield: 31.7 %

Procedure:
(24R,22E)-5,7,22-Ergostatrien-1α,3β,25-triol (Ib) (100 mg, 0.23 mmol) was dissolved in a mixed solution of ether (950 ml) and tetrahydrofuran (50 ml), and the solution was irradiated with high pressure mercury lamp using an 1.5% aqueous potassium nitrate solution as a filter with water cooling in a nitrogen stream for 3 minutes. The residue obtained by distilling off the solvent from the reaction solution was purified by HPLC (column: Lichrosorb® Si60 (7 μm), φ25×250 mm, Merck Co., Ltd.; column effluent: 5% methanol/methylene chloride; flow rate: 8.0 ml/min; detected at 265 nm) to give 28 mg of the previtamin D.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[C:29]3[CH3:37])[CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:20])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[C:29]3[CH3:37])[CH2:27][CH2:28]2)=[O:22])=[CH:6][CH:7]=1
Reactant: CC1=Cc2ccccc2C12CCN(C(=O)c1cnc3c(C(=O)O)cnn3c1Nc1ccc(F)cc1)CC2
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)cc3)c(C(=O)N3CCC4(CC3)C(C)=Cc3ccccc34)cnc12
Yield: 25.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluorophenylamino)-6-(2-methylspiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.100 g, 0.209 mmol) obtained in Example 116, step 2 and ethanesulfonamide (0.113 g, 1.04 mmol), the title compound (0.031 g, 25%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][C:16]([C:17]([OH:19])=O)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][C@@H:27]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[CH3:31][O:30][C:28](=[O:29])[C@@H:27]([NH:26][C:17]([C:16]1[N:15]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=12)=[O:19])[C:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCn2c(-c3ccccc3)nc(C(=O)O)c2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Reaction time: 0.33 h
Yield: 99.7 %

Procedure:
To a solution of 7-(tert-butoxycarbonyl)-3-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid (Intermediate 3B) (2.0 g, 5.82 mmol) in DMF was added (S)-methyl 2-amino-3,3-dimethylbutanoate (1.18 g, 8.15 mmol), followed by DIEA (2.26 g, 17.47 mmol). The resulting mixture was stirred for 20 min and TBTU (2.43 g, 7.57 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with water and extracted with EtOAc, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate/hexanes 10-50% gradient to give Intermediate 22A 2.73 g (98%). LCMS (+ESI) m/z 470.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16]O)[CH2:11][C@H:10]2[O:18][CH3:19])=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1.[Cl:25]C(Cl)Cl.S(Cl)(Cl)=O>N1C=CC=CC=1>[OH2:7].[NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][Cl:25])[CH2:11][C@H:10]2[O:18][CH3:19])=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCO)C[C@H]1OC
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCl)C[C@H]1OC
Product: O
Temperature: 50 °C

Procedure:
To a stirred solution of 5.01 parts of cis-4-amino-5-chloro-N-[1-(2-hydroxyethyl)-3-methoxy-4-piperidinyl]-2-methoxybenzamide in 112.5 parts of trichloromethane were added 1.33 parts of pyridine and 2 parts of thionyl chloride. The whole was stirred and heated for 7 hours at 50° C. and subsequently stirred overnight at room temperature. The reaction mixture was washed with a sodium hydroxide solution and water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated, yielding 9 parts of cis-4-amino-5-chloro-N-[1-(2-chloroethyl)-3- methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate as a residue (interm. 15).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].Br[C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:25]4[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccc(S(N)(=O)=O)cc4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.11) (168 mg, 0.5 mmol) and commercially available 4-bromo-benzenesulfonamide (118 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (136 mg, 55%). MS (ISN) 489.0 [(M−H)−]; mp 275° C.
Reaction SMILES: Br[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:4]=2[O:5][C:6]=1[CH3:7].C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>COCCOC.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>[ClH:20].[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:13]([NH:12][C:8]1[C:4]2[O:5][C:6]([CH3:7])=[C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:3]=2[CH:11]=[CH:10][CH:9]=1)=[O:22]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1-c1ccccn1
Product: Cl
Yield: 50.2 %

Procedure:
A mixture of 3-bromo-7-(2,6-dichlorobenzoylamino)-2-methylbenzo[b]furan (165 mg), 2-(tributylstannyl)pyridine (213 mg) and tetrakis(triphenylphosphine)palladium (10 mg) in 1,2-dimethoxyethane (3 ml) was refluxed for 18 hours. The reaction mixture was evaporated in vacuo and the residue was purified by column chromatography on silica gel. The obtained oil was dissolved in methanolic hydrogen chloride and to the solution was evaporated in vacuo. The residue was crystallized from ethyl acetate to give 7-(2,6-dichlorobenzoylamino)-2-methyl-3-(pyridin-2-yl)benzo[b]furan hydrochloride (45 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[C:11]3([CH2:16][CH2:15]3)[CH2:10][N:9]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)[C:8]=2[N:24]=1.[CH3:25]I>>[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[N:13]([CH3:25])[C:12](=[O:14])[C:11]3([CH2:16][CH2:15]3)[CH2:10][N:9]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)[C:8]=2[N:24]=1
Reactant: CI
Reactant: O=C1Nc2cnc(Cl)nc2N([C@@H]2CCC(F)(F)C2)CC12CC2
Agent: [H-]
Agent: [Na+]
Product: CN1C(=O)C2(CC2)CN([C@@H]2CCC(F)(F)C2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 91.5 %

Procedure:
60% sodium hydride in mineral oil (0.25 g, 6.23 mmol) was added to a mixture of (R)-2′-chloro-9′-(3,3-difluorocyclopentyl)-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (1.95 g, 5.94 mmol) and methyl iodide (0.41 ml, 6.53 mmol) dimethylacetamide (20 mL). The reaction mixture was stirred at room temperature for 25 minutes. Ice was added to the reaction mixture. A solid crashed out and was filtered off, rinsing with water. The solid was dried in a pistol under vacuo for 3 hours. The compound was obtained as a light pink solid (1.863 g, 92% yield).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1>[CH:1]1([NH:6][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: CCOC(=O)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC1CCCC1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
Cyclopentylamine (85.2 g, 1.0 mol) and triethylamine (101.2 g, 1.0 mol) were dissolved in tetrahydrofuran (750 mL) and cooled to 0°-5° C. by means of an ice-water bath. Ethyl bromoacetate (167 g, 1.0 mol) was added dropwise at 0°-5° C. to the solution. After addition the mixture was allowed to warm up to room temperature and then stirred over night at ambient temperature. The precipitated white triethylamine hydrochloride was filtered off and the filtrate concentrated to an oil which was purified over silica gel using hexane/ethyl acetate (8.2) as the eluent. The collected product was dissolved in ether and cooled by means of an ice water bath. Dry hydrogen chloride was bubbled into the solution whereby the HCL salt of the product precipitated. Filtration yielded 138 g of product as a white solid melting at 174°-176° C.