Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH-](CC)CC)C.[Li+].C(OCC)(=O)C.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 83 %

Procedure:
A solution of 2-(S)-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (compound (3), 4.6 g, 0.016 mol) in anhydrous tetrahydrofuran (50 mL, THF) was cooled to 0° C. 1.0 M Lithium triethylborohydride in THF (38 mL, 3.17 g, 0.029 mol) was added dropwise to the reaction mixture while maintaining reaction temperature below 0° C. The reaction mixture was refluxed for overnight (˜11 hour). HPLC showed absence of starting material. Reaction mixture was cooled to 0° C. and ethyl acetate (50 mL) was slowly added followed by addition of distilled water (50 mL) while maintaining temperature below 10° C. The organic layer was separated and washed with distilled water (2×50 mL), 1 M H3PO4(2×50 mL) and saturated NaHCO3 (2×50 mL), dried over MgSO4, filtered, and concentrated to leave an oily residual product (2.46 g, 53.5% yield). 1H NMR (CDCl3): δ 1.16 (d, 3H, CH3), 1.47 (s, 9H, 3×CH3), 1.50–1.82 (m, 2H, CH2), 1.84–2.03 (m, 2H, CH2), and 3.86 (m, 1H, CH).
Reaction SMILES: C1(C2(C(O)=O)CCCC2)C=CC=CC=1.[CH3:15][CH:16](C)[CH:17]([C:40]1C=CC=C[CH:41]=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19].C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[CH2:40]([CH:17]([CH2:16][CH3:15])[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19])[CH3:41]
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Agent: O=C(O)C1(c2ccccc2)CCCC1
Product: CCC(CC)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21

Procedure:
The title compound was prepared by substituting 2-ethylbutanoic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.90 (d, J=6.7, 1H), 7.71 (s, 1H), 7.61 (d, J=7.7, 1H), 7.54 (d, J=7.7, 1H), 7.46 (t, J=7.7, 1H), 4.51-4.43 (m, 1H), 3.49 (s, 2H), 2.83 (ddd, J=2.9, 7.8, 16.8, 1H), 2.75 (dd, J=2.9, 9.5, 1H), 2.52-2.43 (m, 1H), 2.37 (dd, J=2.9, 9.1, 1H), 2.35-2.30 (m, 1H), 2.25 (dd, J=7.6, 9.4, 1H), 2.01 (tt, J=4.8, 9.5, 1H), 1.89 (dt, J=7.3, 11.6, 1H), 1.77 (ddt, J=7.5, 9.3, 15.2, 2H), 1.70-1.60 (m, 2H), 1.51-1.37 (m, 2H), 1.34-1.26 (m, 1H), 0.95 (t, J=7.4, 3H), 0.83 (t, J=7.4, 3H); MS (ESI+) m/z 383 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Li+].[F:20][C:21]([F:37])([F:36])[C:22]1[N:27]=[C:26]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33]([O-])=[O:34])[CH:25]=[CH:24][CH:23]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:21]([F:37])([F:20])[F:36])[N:27]=3)=[O:34])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C([O-])c1ncoc1-c1cccc(C(F)(F)F)n1
Agent: [Li+]
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(C(F)(F)F)n3)n2)o1

Procedure:
Following general procedure Z3 followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(6-trifluoromethyl-pyridin-2-yl)-oxazole-4-carboxylic acid lithium salt. LC-MS-conditions 01: tR=0.90 min; [M+H]+=445.99.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[Br:12]N1C(=O)CCC1=O>C(Cl)Cl>[Br:12][C:7]1[CH:6]=[C:5]([O:9][CH3:10])[C:4]([OH:11])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cccc(OC)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1cc(Br)cc(OC)c1O
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a cooled (−78° C.) solution of 2,6-dimetoxyphenol (13)(15 g, 97.35 mmol) in CH2Cl2 (200 ml) was added N-bromosuccinimide (17.4 g, 97.35 mmol) portionwise over twenty minutes. The reaction mixture was stirred at −78° C. under an inert atmosphere for four hours before being allowed to warm to room temperature where it was stirred for a further 16 hours. The solvent was then removed in vacuo to give a slurry that was purified by flash chromatography (SiO2) (7:3—CH2Cl2:Hexanes) and then re-crystallised from CH3Cl/hexanes to give the title compound as a white solid that was analytically clean (9.66 g, 42.57%). m/z (LC-MS, ESP): 231 [M−H]−, R/T=3.17 mins
Reaction SMILES: [F:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]([OH:19])=[C:6]([CH:18]=1)[C:7]([C:9]1[CH:14]=[C:13]([F:15])[C:12]([OH:16])=[CH:11][C:10]=1O)=[O:8]>O>[F:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[O:19][C:10]3[C:9](=[CH:14][C:13]([F:15])=[C:12]([OH:16])[CH:11]=3)[C:7](=[O:8])[C:6]=2[CH:18]=1
Reactant: O=C(c1cc(F)c(O)cc1O)c1cc(F)c(O)cc1O
Solvent: O
Product: O=c1c2cc(F)c(O)cc2oc2cc(O)c(F)cc12
Yield: 82.5 %

Procedure:
Compound 7 (0.75 g, 2.66 mmol) was heated in a sealed tube with H2O (30 mL) at 200-220 0° C. for 2-3 h. On cooling, 2,7-difluoro-3,6-dihydroxyxanthone 8 precipitated out. The product was collected by filtration and washed with H2O to give 8 (0.58 g, 83%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 11.4 (s, 2H), 7.67 (d, 2H, J=10.9 Hz), 6.96 (d, 2H, J=7.1 Hz); 13C NMR (75 MHz, DMSO-d6) δ 173.1, 153.1, 152.0, 151.8, 150.4, 147.2, 112.6, 112.5, 111.1, 110.8, 104.7, 104.6; 19F NMR (282 MHz, DMSO-d6) δ −139.0 (dd, 2F); mass spectrum, calculated for C13H6F2O4 (MH+) 265.0, Found 264.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:28]1[S:32][CH:31]=[C:30]([C:33](O)=[O:34])[CH:29]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].[F:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[F:45])[CH2:40][NH2:41].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>C(Cl)Cl>[F:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[F:45])[CH2:40][NH:41][C:33]([C:30]1[CH:29]=[C:28]([C:7]2[C:8]3[C:15](=[O:16])[N:14]4[C@H:10]([C:9]=3[N:17]=[C:18]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]4)[S:32][CH:31]=1)=[O:34]
Reactant: NCc1ccc(F)c(F)c1
Reactant: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1cc(C(=O)O)cs1)C(=O)N1CCC[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1cc(C(=O)NCc3ccc(F)c(F)c3)cs1)C(=O)N1CCC[C@@H]21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-{(9aS)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl}-3-thiophenecarboxylic acid (0.100 g, 0.202 mmol) was dissolved in CH2Cl2. 3,4-difluorobenzylamine (0.036 mL, 0.303 mmol) was added followed by EDCI (0.047 g, 0.243 mmol) and HOBt (0.033 g, 0.243 mmol). After 14 h of stirring at ambient temperature the reaction mixture was poured onto 5% HCl solution and extracted with CH2Cl2. The organics were washed with sat'd NaHCO3, brine and then dried (Na2SO4), filtered and concentrated to a brown residue. Chromatography on silica gel using 3:1 EtOAc:Hexanes eluted the product to provide the title compound upon concentration as a white solid (0.065 g, 0.105 mmol, 52% yield): 1H NMR (CDCl3, 400 MHz) δ 8.06 (s, 1H), 7.48 (s, 1H), 7.17–7.03 (m, 5H), 6.97 (t, J=8.6 Hz, 2H), 6.96 (m, 1H), 4.69 (dd, J=10.4, 6.3 Hz, 1H), 4.51 (d, J=5.8 Hz, 2H), 4.16 (dd, J=14.3, 7.0 Hz, 2H), 3.73–3.63 (m, 1H), 3.42–3.36 (m, 1H), 3.19–2.99 (m, 4H), 2.51–2.43 (m, 1H), 2.39–2.27 (m, 2H), 1.41–1.34 (m, 1H), 1.09 (t, 7.1 Hz); ESMS m/z 620 (M+H)+, 618 (M−H)+; Anal. Calcd. For C33H28F3N3O4S: C, 63.96; H, 4.55; N, 6.78; found C, 64.03; H, 4.58; N, 6.73.
Reaction SMILES: [CH:1]#[C:2][CH3:3].[F:4][C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[CH2:8][N:9]1[C:21]2[CH2:20][CH2:19][C@@H:18]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([CH:28]=[N:29][OH:30])[CH:14]=2>C(Cl)Cl.[O-]Cl.[Na+]>[F:4][C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[CH2:8][N:9]1[C:21]2[CH2:20][CH2:19][C@@H:18]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([C:28]1[CH:1]=[C:2]([CH3:3])[O:30][N:29]=1)[CH:14]=2
Reactant: O=C(N[C@@H]1CCc2c(c3cc(C=NO)ccc3n2Cc2cccc(F)c2)C1)C1CC1
Reactant: C#CC
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: Cc1cc(-c2ccc3c(c2)c2c(n3Cc3cccc(F)c3)CC[C@@H](NC(=O)C3CC3)C2)no1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
Bubble propyne gas through a solution of (R)-cyclopropanecarboxylic acid[9-(3-fluoro-benzyl)-6-(hydroxyimino-methyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide (Example 203) (0.065 g, 0.16 mmol) in methylene chloride and NaOCl solution maintained in a sealed tube. Cap the tube and stir at 23° C. for 16 h. Partition the reaction between methylene chloride and water. Separate and dry the organic portion over Na2SO4 to give 0.045 g of a tan solid. Purify by silca gel chromatography, eluting with 20-80% EtOAc/gradient to give an 0.030g (42%) of an off-white solid. mp: 190-192° C.; MS (ES): m/z 444 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][CH2:13][CH3:14])[N:3]=1.[F:15][C@@H:16]1[C@@H:20]([CH2:21][OH:22])[O:19][C@@H:18](N2C=CC(=O)NC2=O)[CH2:17]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:18]2[O:19][C@H:20]([CH2:21][OH:22])[C@@H:16]([F:15])[CH2:17]2)=[C:4]([NH:11][CH2:12][CH2:13][CH3:14])[N:3]=1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CCCNc1nc(N)nc2[nH]cnc12
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCNc1nc(N)nc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1
Temperature: 45 °C
Reaction time: 120 h
Yield: 11.7 %

Procedure:
2-Amino-6-propylamino-9H-purine (0.50 g, 2.6 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in 50 ml, 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky et al., Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 5 days, 192 ml MeOH was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (9:1). Solvent was removed and lyophilization yielded 0.08 g of 2-amino-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-(propylamino)-9H-purine (11%): mp 153° C.; TLC Rf 0.60 (silica gel, MeCN:15N NH4OH:H2O/85:5:10);
Reaction SMILES: [OH-].[Na+].[NH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11]([Cl:14])[CH:12]=2)[C:7](=[O:16])[C:6]([C:17]([O:19]CC)=[O:18])=[CH:5]1.C(O)(=O)C>O>[NH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11]([Cl:14])[CH:12]=2)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]1
Reactant: CCOC(=O)c1cn(N)c2cc(Cl)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reaction time: 2 h
Yield: 85.6 %

Procedure:
Sodium hydroxide (0.91 g, 0.0228 mole) was dissolved in 100 ml of water, and 2.6 g (0.0091 mole) of ethyl 1-amino-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate was added. The mixture was stirred on a steam bath for two hours and the hot solution was neutralized with acetic acid (1.6 ml). The suspension of solid was stirred at room temperature for about sixteen hours, and the solid was collected by filtration and washed with water. The product was recrystallized from dimethylformamide to give 2.0 g of 1-amino-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, beige powder, m.p. 312°-315° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl>[C:1]1([CH2:7][C:8]([Cl:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cl)Cc1ccccc1
Reaction time: 24 h
Yield: 99.6 %

Procedure:
A mixture of 27.2 g (0.2 moles) phenylacetic acid and 28 g (0.22 moles) oxalyl chloride in 150 ml methylene chloride were stirred for 24 hours. Excess reagent and solvent were removed by stripping to give 30.8 g of phenylacetyl chloride, which was used in step (b) without further isolation.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.[CH3:12][C:13]([CH3:25])([C:16](=[O:24])[CH:17]([N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[CH3:18])[CH2:14][F:15]>C1COCC1>[CH3:25][C:13]([CH3:12])([C:16]([CH:17]([N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[CH3:18])([OH:24])[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:14][F:15]
Reactant: C#CCCCC
Reactant: CC(C(=O)C(C)(C)CF)n1cncn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC#CC(O)(C(C)n1cncn1)C(C)(C)CF
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
To a stirred solution of hex-1-yne (1.23 g, 15 mmol) in dry THF (40 ml) was added n-butyl lithium (6 ml of 2.6M, 15 mmol) at -78° C. under a nitrogen atmosphere. After 15 minutes, a solution of 2,2-dimethyl-1-fluoro-4-(1H-1,2,4-triazol-1-yl)-pentan-3-one (2.5 g, 13 mmol) in dry THF (20 ml) was added dropwise. Upon complete addition the mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was then poured onto ice and extracted with ether (2×250 ml). The ethereal solution was washed with saturated brine solution then dried over anhydrous magnesium sulphate and the solvent removed. The resulting yellow oil was chromatographed (silica gel, petrol/diethyl ether elution) to give a yellow gum (2.0 g, 56.5%) which was a mixture of the RS/SR and the RR/SS forms. This gum was then purified by preparative chromatography to give the pure RS/SR form as a white solid (0.24 g, 6.8%), mp. 72°-74° C. (Found: C, 63.5; H, 9.0; N, 15.0C15H24FN3O requires C, 64.1; H, 8.5; N, 14.95%); IR 3200, 2950, 2225, 1360, 1280, 1200, 1140, 1000, 870, 680 cm-1 ; NMR (90 MHz; CDCl3) 0.8 (6H, s); 0.9 (3H, t, J 7 Hz); 1.2-1.56 (4H, m); 1.72 (3H, d, J 6.3 Hz); 2.24 (2H, m); 3.8 (1H, br); 4.36 (2H, dq, J 46.8 and 6.3 Hz), 4.8 (1H, q, J 6.3 Hz); 7.95 (1H, s); 8.24 (1H, s); m/z 282 (M+H+) 206, 185, 109, 97 (100%), 82. The RR/SS component could not be isolated in a pure state thus, a 1:1 mixture of the RS/SR and RR/SS forms was obtained as a yellow oil (0.34 g, 9.6%); NMR (90 MHz; CDCl3) 0.8 (6H, s); 0.92 (3H, t, J 7 Hz); 1.2-1.56 (4H, m); 1.66 (3H, d, J 6.3 Hz); 2.13 (2H, m); 3.8 (1H, br); 4.36 (2H, dq, J 46.8 and 6.3 Hz), 4.76 (1H, q, J 6.3 Hz); 7.93 (1H, s); 8.26 (1H, s); m/z 282 (M+H+), 206, 185, 109, 97 (100%), 82.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@@H:4]1[C:9]1[N:13]2[C:14]3[CH:20]=[CH:19][NH:18][C:15]=3[N:16]=[CH:17][C:12]2=[CH:11][N:10]=1.CCN(C(C)C)C(C)C.[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[N:38]=[C:39]=[O:40]>C(Cl)Cl>[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[NH:38][C:39]([N:6]1[CH2:7][CH2:8][C@@H:3]([CH3:2])[C@@H:4]([C:9]2[N:13]3[C:14]4[CH:20]=[CH:19][NH:18][C:15]=4[N:16]=[CH:17][C:12]3=[CH:11][N:10]=2)[CH2:5]1)=[O:40]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: C[C@@H]1CCNC[C@@H]1c1ncc2cnc3[nH]ccc3n12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCN(C(=O)Nc2ccc(F)cc2F)C[C@@H]1c1ncc2cnc3[nH]ccc3n12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 20.1 %

Procedure:
A round bottom flask was charged with 1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (0.05 g, 0.17 mmol, Example #5 Step J) and DIEA (0.03 mL, 0.17 mmol) in DCM (1.6 mL). The reaction mixture was stirred for about 5 min at ambient temperature then 2,4-difluoro-1-isocyanatobenzene (0.02 mL, 0.17 mmol) was added and the reaction mixture was stirred at ambient temperature for about 18 h. The reaction mixture was diluted with DCM (5 mL) and washed with water (2 mL). The aqueous layer was back extracted with DCM (2 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The material was purified by RP-HPLC (Table 1, Method e) to afford (3R,4R)-N-(2,4-difluorophenyl)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxamide (0.014 g, 20%): LC/MS (Table 1, Method j) Rt=1.77 min; MS m/z 411 (M+H)+.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([SH:11])[CH:8]=[CH:9][CH:10]=1.[C:12]([C:14]1[C:19]([CH2:20]Br)=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>CO>[C:12]([C:14]1[C:19]([CH2:20][S:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([Cl:4])[CH:6]=2)=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]
Reactant: Sc1cccc(Cl)c1
Reactant: N#Cc1ncccc1CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ncccc1CSc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred, cloudy solution of sodium methoxide (14.7 g, 0.27 mol) in methanol (450 mL), contained in a water bath, add a solution of 3-chlorothiophenol (39.5 g, 0.27 mol) in methanol (95 mL). To the resultant solution add a solution of 2-cyano-3-(bromomethyl)pyridine (48.9 g, 0.25 mol) in methanol (195 mL), and stir the reaction mixture at room temperature for 1 h. Concentrate the reaction mixture under reduced pressure, add 500 mL of ether to the residue, stir, and filter to remove the sodium bromide. Evaporate ether under reduced pressure to obtain the title compound as an amber oil, which may be used without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:19])[CH:16]=3)[N:11]([CH2:20][CH2:21][OH:22])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH2:23]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:19])[CH:16]=3)[N:11]([CH2:20][CH2:21][O:22][S:32]([CH3:31])(=[O:34])=[O:33])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:24]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)C(=O)C1CCCc2c1c1cc(F)ccc1n2CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)C1CCCc2c1c1cc(F)ccc1n2CCOS(C)(=O)=O
Temperature: 0 °C
Yield: 28.9 %

Procedure:
To a solution of 6-fluoro-9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (37) (460 mg, 1.4 mmol) in dichloromethane (20 mL) was added pyridine (1.11 g, 14.0 mmol, 1.1 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (722 mg, 6.3 mmol, 0.5 mL) was added. The reaction was allowed to warm to room temperature overnight. The mixture was washed with 2 N HCl (2×30 mL) and water (2×30 mL), dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (0-100% (B), 10 g, 45 CV, 30 mL/min) then triturated with diethyl ether to afford 166 mg (30%) of methanesulfonic acid 2-(4-diethylcarbamoyl-6-fluoro-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester as a white solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 12.9, 15.0, 21.1, 27.7, 36.1, 36.7, 40.6, 41.7, 67.8, 103.3 (d, JCF=23 Hz), 108.7, 109.0, 109.1, 109.4 (d, JCF=5 Hz), 126.9 (d, JCF=10 Hz), 132.4, 138.4, 156.1, 159.2, and 173.3.
Reaction SMILES: [CH:1](=[N:3][C:4]([CH2:11][CH2:12][CH3:13])([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:6][CH3:7])[CH3:2].[BH4-].[Na+].[OH-].[Na+]>CO>[CH2:1]([NH:3][C:4]([CH2:11][CH2:12][CH3:13])([CH2:5][CH2:6][CH3:7])[CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: CC=NC(CCC)(CCC)CCC
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(CCC)(CCC)NCC
Temperature: 5 °C

Procedure:
Into a 500-ml three-necked flask, fitted with a mechanical stirrer and a condenser, were introduced 17.6 g (0.096 mol) of N-ethylidene-1,1-di-n-propyl-n-butylamine, prepared as described hereabove, and 150 ml of methanol. To this solution when cooled, 7.6 g (0.2 mol) of sodium borohydride were added slowly and while stirring. After this operation, the mixture was maintained at a temperature of 5° C. for 30 minutes and then progressively heated under reflux. Thirty minutes later, the methanol was evaporated off under vacuum and 200 ml of water were added to the residue so obtained followed by 100 ml of a solution of sodium hydroxide (d=1.38). The organic fraction was extracted with ether and the solution was distilled under reduced pressure.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (337 mg, 1.0 mmol) and 4-bromobenzenesulfonamide [CAS 701-34-8] (307 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (150 mg, 30%). MS (ISP) 493.2[(M+H)+]; mp 254° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:31]#[C:30][CH2:29][OH:32])[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: C#CCO
Reactant: Cc1ccc(I)cc1Cl
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1ccc(C#CCO)cc1Cl
Temperature: 25 °C
Reaction time: 25 h

Procedure:
A mixture of 2-chloro-4-iodotoluene (5.00 g), copper(I) iodide (75.4 mg), triphenylphosphine (260 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (410 mg), propargyl alcohol (1.29 ml), diisopropylethylamine (13.8 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 25 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-80:20) to give the object product (2.80 g) as a brown oil.