Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH3:5])[C:3]#[N:4].Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:17]([C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:27])[C:16]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=3[O:44][CH2:45][CH3:46])=[N:15]2)=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:17]([C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH2:5][CH2:2][C:3]#[N:4])[CH2:30][CH2:29]3)=[O:27])[C:16]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:43])[F:42])=[CH:36][C:35]=3[O:44][CH2:45][CH3:46])=[N:15]2)=[CH:12][CH:13]=1
Reactant: CC(Br)C#N
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromopropionitrile (10 uL, 0.120 mmol) was added to a mixture of [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[piperazin-1-yl]-methanone hydrochloride and diisopropylethylamine (42 uL, 0.240 mmol) in dimethylformamide (1.0 mL). The reaction was stirred at room temperature overnight. Evaporation of the solvent and purification of the crude residue by flash chromatography over silica gel using 1-2% methanol in methylene chloride gave 3-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-propionitrile, which was dissolved in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to give 3-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-propionitrile hydrochloride as an off-white powder (20 mg, 39% yield). LR-MS (APCI): 644.4 [(M+H)+].
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[NH:31]1[CH:35]=[C:34]([CH:36]=[O:37])[CH:33]=[N:32]1>C(#N)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:7]2[C:6]3[C:11](=[CH:12][C:3]([CH2:2][N:31]4[CH:35]=[C:34]([CH:36]=[O:37])[CH:33]=[N:32]4)=[CH:4][CH:5]=3)[N:10]=[C:9]([C:13]#[N:14])[CH:8]=2)=[CH:16][CH:17]=1
Reactant: N#Cc1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2n1
Reactant: O=Cc1cn[nH]c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(-c2ccc(F)cc2)c2ccc(Cn3cc(C=O)cn3)cc2n1
Yield: 52.7 %

Procedure:
7-(Bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-1, 100.0 mg, 0.293 mmol, 1.0 equiv.), DIEA (0.051 ml, 0.293 mmol, 1.0 equiv.), and 1-H-pyrazole-4-carbaldehyde (33.8 mg, 0.352 mmol, 1.2 equiv.) were added to acetonitrile (1.0 mL) in a microwave reaction vessel and the resulting mixture was irradiated with microwave at 180° C. for 30 minutes. The reaction mixture was cooled and concentrated and the residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 4-(4-fluorophenyl)-7-[(4-formyl-1H-pyrazol-1-yl)methyl]quinoline-2-carbonitrile (3-8, 55.0 mg, 52.7%) as a colorless solid. LRMS m/z (M+H)+ 357.1 found, 357.1 required.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[CH3:39])=[O:15])[CH2:10][C@@H:9]1[CH2:40][C:41](O)=[O:42])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:44][CH2:45][C:46]([CH3:51])([CH3:50])[C:47]([NH2:49])=[O:48].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CC(=O)OCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17]=2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[CH3:39])=[O:15])[CH2:10][C@@H:9]1[CH2:40][C:41](=[O:42])[NH:44][CH2:45][C:46]([C:47](=[O:48])[NH2:49])([CH3:51])[CH3:50])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(CN)C(N)=O
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)NCC(C)(C)C(N)=O)C1
Temperature: 25 °C
Reaction time: 60 h
Yield: 91.6 %

Procedure:
The compound of step 5 (0.176 g, 0.30 mmol) was dissolved in 2.5 ml of anhydrous DCM at 0° C. 3-Amino-2,2-dimethyl-propionamide (0.044 g, 0.38 mmol), EDIA (0.13 ml, 0.75 mmol) and TBTU (0.120 g, 0.38 mmol) were added and the solution was stirred at room temperature for 60 h. EA (15 ml) was then added and the solution was washed with water, 1 N hydrochloric acid, a saturated solution of sodium hydrogencarbonate and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (EA/MOH, 100:0, then 97:5, then 95:5) to give 0.188 g of the title compound as a greenish-brown wax.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:8]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C@H:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])[CH2:10][CH2:11][CH:12]=[CH2:13])=[N:4][CH:5]=[CH:6][N:7]=1.[C:30]([O:34][CH3:35])(=[O:33])C=C>C(Cl)Cl>[Br:1][C:2]1[C:3]([C@@H:8]([NH:22][C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29])[C@H:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])[CH2:10][CH2:11]/[CH:12]=[CH:13]/[C:30]([O:34][CH3:35])=[O:33])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: C=CCC[C@@H](c1cccc(F)c1F)[C@H](NC(=O)OC(C)(C)C)c1nccnc1Br
Reactant: C=CC(=O)OC
Solvent: ClCCl
Product: COC(=O)/C=C/CC[C@@H](c1cccc(F)c1F)[C@H](NC(=O)OC(C)(C)C)c1nccnc1Br
Yield: 84.1 %

Procedure:
In a 250 mL round-bottomed flask was dissolved tert-butyl (1S,2S)-1-(3-bromopyrazin-2-yl)-2-(2,3-difluorophenyl)hex-5-enylcarbamate (354.6 mg, 0.757 mmol) in methylene chloride (16 mL) to give a colorless solution. Methyl acrylate (0.21 mL, 2.3 mmol) and Grubbs-If catalyst (32.1 mg, 0.038 mmol) were added, and the mixture was stirred under reflux for 3 h under nitrogen. TLC showed complete conversion. Volatile components were removed in vacuo and the residue was purified by flash column chromatography upto 50% ethyl acetate/hexane to afford the desired product (335 mg, 84%) as a colorless oil: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.31 (s, 1H) 8.28 (s, 1H) 6.98-7.14 (m, 3H) 6.80-6.94 (m, 1H) 5.76 (d, J=16.56 Hz, 1H) 5.59-5.71 (m, 1H) 5.42 (d, 0.1-9.54 Hz, 1H) 3.71 (s, 3H) 3.59-3.69 (m, 1H) 2.09-2.29 (m, 2H) 1.96-2.04 (m, 1H) 1.83-1.95 (m, 1H) 1.37 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:11])([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].O>CN(C=O)C>[Si:21]([O:4][CH2:3][C:2]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)([F:1])[F:11])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(F)(F)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(F)(F)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2-difluoro-2-(pyridin-4-yl)-ethanol (0.15 g) prepared in (2) in DMF (3.0 mL) were added imidazole (0.076 g) and tert-butyldimethylchlorosilane (0.15 g). The reaction mixture was stirred at RT for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: ethyl acetate) to give the title compound.
Reaction SMILES: BrC1C(F)=CC=C2C=1CC[NH:6]C2CC(OC)=O.S(=O)(=O)(O)O.[C:23]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:37])[C:32]=2[Br:36])[CH:27]1[CH2:38][C:39]([O:41]C)=O)(=[O:25])[CH3:24].C([O-])(O)=O.[Na+]>O.CO>[Br:36][C:32]1[C:31]([F:37])=[CH:30][CH:29]=[C:28]2[C:33]=1[CH2:34][CH2:35][N:26]1[C:23](=[O:25])[CH2:24][NH:6][C:39](=[O:41])[CH:38]=[C:27]12
Reactant: COC(=O)CC1NCCc2c1ccc(F)c2Br
Reactant: COC(=O)CC1c2ccc(F)c(Br)c2CCN1C(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1C=C2c3ccc(F)c(Br)c3CCN2C(=O)CN1
Temperature: 25 °C

Procedure:
methyl 2-(5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. MeOH (620 mL) was cooled to −15° C. and conc. Sulfuric acid (73.7 mL, 1383 mmol) was added slowly (exotherm) under cooling. To this solution, methyl 2-(2-acetyl-5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (47.6 g, 138 mmol) was added and the reaction mixture was stirred under reflux for 96 h. The reaction mixture was cooled to RT and slowly added to a solution of NaHCO3 (244 g) in water (500 mL). The slightly basic aqueous solution was extracted with AcOEt (3×). The combined organic layers were washed with saturated aqueous NaHCO3 and brine. The organic layer was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was dried under high vacuo to yield the title compound as yellow foam (41.58 g) which was used without further purification. UPLC-MS: MS 302.1/304.1 (M+H+); UPLC rt 0.51 min.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl-].C([Al+]CC)C.[CH3:17][C:18]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>ClCCl>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:25]([C:18]3([CH3:17])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:26])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: CC1(C(=O)Cl)CCCCCC1
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
A suspension of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (100 mg, 0.505 mmol) in anhydrous dichloromethane (10 ml) was cooled to 0° C. under N2. Diethyl aluminum chloride (1M in hexanes, 1.50 ml, 1.50 mmol) was added quickly, and the reaction mixture was stirred for 30 minutes. 1-Methyl-cycloheptanecarbonyl chloride (882 mg, 5.05 mmol) was added dropwise, and the reaction mixture was refluxed overnight. The reaction mixture was cooled to 0° C. and quenched with saturated aqueous NaHCO3. The biphasic solution was concentrated, and the remaining aqueous solution was extracted with ethyl acetate. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a pale brown solid. The residue was purified by silica gel chromatography using 19-74% EtOAc in hexanes as eluant providing 55 mg (32%) of (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cycloheptyl)-methanone as a white solid. MP 197.7-198.2° C., M+H=336.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][CH:25]([C:28]([OH:30])=O)[CH2:24][CH2:23]2)=[O:20])[C:14]=1[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>CN(C=O)C>[N:65]1([C:28]([CH:25]2[CH2:24][CH2:23][CH:22]([NH:21][C:19]([C:15]3[C:14]([CH3:31])=[C:13](/[CH:12]=[C:5]4\[C:6](=[O:11])[NH:7][C:8]5[C:4]\4=[CH:3][C:2]([F:1])=[CH:10][CH:9]=5)[NH:17][C:16]=3[CH3:18])=[O:20])[CH2:27][CH2:26]2)=[O:30])[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1
Reactant: C1COCCN1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CCC(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To the solution of 4-({5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-cyclohexanecarboxylic acid in 20 mL of DMF were added HATU (0.161 g, 0.424 mmol), DIEA (0.072 mL, 0.424 mmol) and morpholine (0.0737 g, 0.847 mmol). The reaction mixture was stirred at r.t. overnight. LC-MS was used to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethyl amine/methanol (5 mL). The precipitate was collected by filtration, washed with methanol and dried in vacuum to give title compound (69 mg, 32.9% yield) as an orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.66 (s, 1H), 10.87 (s, 1H), 7.71-7.77 (m, 2H), 7.53-7.55 (d, 1H), 6.81-6.92 (m, 2H), 3.95-3.96 (m, 1H), 3.29-3.54 (m, 8H), 2.64-2.67 (m, 1H), 2.39-2.41 (ds, 6H), 1.47-1.88 (m, 8H). LC/MS: 495.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:9]=2)=[C:4]([O:45][CH3:46])[CH:3]=1.[N-:47]=[C:48]=[O:49].[K+]>O.C(O)(=O)C>[CH3:46][O:45][C:4]1[CH:3]=[C:2]([NH:1][C:48]([NH2:47])=[O:49])[CH:7]=[CH:6][C:5]=1[C:8]1[C:16]2[C:15]([NH:17][C@H:18]([C:20]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:24](=[O:32])[C:23]4=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]4[N:21]=3)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=2[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:43])([CH3:42])[CH3:44])[CH:9]=1
Reactant: COc1cc(N)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Reactant: [N-]=C=O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(NC(N)=O)ccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a suspension of (S)-2-(1-((5-(4-amino-2-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) in water (0.40 mL) and acetic acid (0.20 mL) was added potassium isocyanate (19 mg, 0.23 mmol) according to the method described in Preparation 181 but stirring at 60° C. overnight. The residue was purified using SP1® Purification System (0% to 100% n-hexane-ethyl acetate) to obtain 34 mg (61% yield) of the title compound.
Reaction SMILES: [C:1]1([CH3:38])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C@@H:13](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][C@@H:11]2[CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1(C)C=CC=CC=1>[C:1]1([CH3:38])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:14][C@H:13]3[CH2:12][C@@H:11]2[CH2:26][N:46]3[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](OS(=O)(=O)c3ccc(C)cc3)CN2S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2C[C@H]3C[C@@H]2CN3Cc2ccccc2)cc1
Reaction time: 3 h
Yield: 90 %

Procedure:
A mixture of 2697 g (4.653 moles) of (2R, 4S)-1-(4-toluenesulfonyl)-2-(4-toluenesulfonyloxymethyl)-4-(4-toluenesulfonyloxy)-pyrrolidine and 1640 g (15.304 moles) of benzylamine in 15 L of toluene was heated under reflux. After 6 hours 100 g of benzylamine were added and the reflux continued for 3 hours. The mixture was cooled, filtered and the residue was washed with 5 L of toluene. The combined organic layers were evaporated to dryness and the resulting solid was taken up with 2 L of isopropanol. After cooling the product was filtered, washed with cold isopropanol and dried under reduced pressure to give 1434 g of the titled compound. (90%). M.P. =124° C. [α]D =-15.72° (c=1.6, acetone)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:17])=O>CN(C=O)C.O1CCOCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([Cl:17])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(Cl)c1ccc2ncccc2c1

Procedure:
Under nitrogen, a 1 L round bottom flask, equipped with septum and drying tube attached to a gas scrubber setup, was charged with 25.4 g (146.5 mmol) quinoline-6-carboylic acid. 1,4-Dioxane (250 mL) was added along with 10 drops of DMF. Inside a glovebox, oxalyl chloride (25.1 g, 197.8 mmol, 1.35 eq) was weighed into a septum vial. The vial was closed, removed from the glovebox, and the weighed oxalyl chloride was added, under nitrogen, to the reaction, in portions, via syringe. The reaction was stirred until most of the gas development ceased. The reaction remained stirring at room temperature overnight. The volatiles were removed using a rotary evaporator. Trace HCl was removed by addition of several aliquots of dry toluene, which were consecutively evaporated using the rotary evaporator. The final product was obtained in form of a colorless to slightly yellow powder (28.0 g, 146.4 mmol, 100%). 1H-NMR: (500 MHz, CDCl3) δ 9.35 (dd, J=5.2, 1.5 Hz, 1H), 9.09 (d, J=8.5 Hz, 1H), 9.09 (d, J=9.0 Hz, 1H), 9.01 (d, J=2.0 Hz, 1H), 8.64 (dd, J=9.1, 2.0 Hz, 1H), 8.14 (dd, J=8.4, 5.2 Hz, 1H); 13C-NMR (126 MHz, CDCl3) δ 122.92, 123.90, 128.21, 133.44, 133.79, 134.55, 140.95, 146.44, 147.11, 166.69.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:25][C:26]([O:40][CH2:41][CH3:42])([CH3:39])[C:27](OC1C=CC([N+]([O-])=O)=CC=1)=[O:28])[CH3:24]>CN(C1C=CN=CC=1)C.C(#N)C.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[NH:22][C:27](=[O:28])[C:26]([O:40][CH2:41][CH3:42])([O:25][CH2:23][CH3:24])[CH3:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Reactant: CCOC(C)(OCC)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(C)(OCC)C(=O)Nc1cc(C)ccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 61.8 %

Procedure:
4-(2-Amino-4-methyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 1.31 mmol), p-nitrophenyl 2,2-diethoxyproprionate (1.00 g, 3.50 mmol), and DMAP (1.00 g, 8.2 mmol) were combined in acetonitrile (3 mL) and heated in an oil bath at 80° C. for 2 h. The mixture was cooled, diluted with diethyl ether (100 mL), washed once each with saturated aqueous NH4Cl and water, three times with 5% aqueous sodium hydroxide solution, once with brine and dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was adsorbed on a silica gel pad, and the pad was eluted with 25% ethyl acetate in hexanes to give 4-[2-(2,2-diethoxy-propionylamino)-4-methyl-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (550 mg, 0.81 mmol, 62%) of a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH:4]=O.[CH3:8][CH:9]([CH3:13])[C@H:10]([NH2:12])[CH3:11]>CO.[Pd].O>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:12][C@@H:10]([CH:9]([CH3:13])[CH3:8])[CH3:11]
Reactant: CC(C)[C@@H](C)N
Reactant: COC(C=O)OC
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC(CN[C@H](C)C(C)C)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2-Dimethoxyacetaldehyde (60% in water, 8.7 mL) was added to (R)-3-methylbutan-2-amine (5.0 g) in methanol (25 mL) and the mixture stirred at ambient temperature overnight. A slurry of palladium on carbon (5%, 1.2 g) in water (10 mL) was added and the mixture was hydrogenated at 5 bar pressure with stirring for 3 hours. The mixture was filtered through Celite and the filter pad washed with methanol (3×100 mL). The combined filtrate and washings were concentrated to a volume of −10 mL and then toluene (200 mL) was added. The mixture was concentrated, more toluene (200 mL) was added and the mixture was concentrated once more to give the titled compound as a yellow oil. Yield 8.0 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:23]1[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:23]4[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (73 mg, 0.25 mmol) and 5-bromo-thiophene-2-sulfonic acid amide (61 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (52 mg, 45%). MS (ISP) 445.4 [(M+H)+]; mp 218-220° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:25][C:19]3[N:20]=[CH:21][NH:22][C:23](=[O:24])[C:18]=3[C:17]=2[CH3:26])=[O:15])[CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=1[F:45])=[O:36]>CC#N>[F:45][C:39]1[CH:40]=[C:41]([F:44])[CH:42]=[CH:43][C:38]=1[NH:37][C:35](=[O:36])[CH2:34][N:22]1[C:23](=[O:24])[C:18]2[C:17]([CH3:26])=[C:16]([C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH2:13][CH2:12]3)=[O:15])[S:25][C:19]=2[N:20]=[CH:21]1
Reactant: Cc1c(C(=O)N2CCN(c3ccccc3F)CC2)sc2nc[nH]c(=O)c12
Reactant: O=C(CCl)Nc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(C(=O)N2CCN(c3ccccc3F)CC2)sc2ncn(CC(=O)Nc3ccc(F)cc3F)c(=O)c12
Temperature: 130 °C
Yield: 34.6 %

Procedure:
To a suspension of 6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one, (0.06 g, 0.16 mmol) in CH3CN (0.5 mL) was added K2CO3 (22 mg, 0.16 mmol), KI (29 mg, 0.17 mmol), and 2-chloro-N-(2,4-difluorophenyl)acetamide, (36 mg, 0.16 mmol). The reaction mixture was heated at 130° C. for 25 min in a microwave reactor. The reaction was quenched with H2O (25 mL) and the aqueous layer was extracted with EtOAc (25 mL). The organic layer was washed with brine (25 mL), dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography (Et2O:DCM, 1:1) providing 30 mg of pure N-(2,4-difluorophenyl)-2-(6-(4-(2-fluorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetamide, (yield: 35%).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[CH:6]=[CH:7][C:8]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:4]=2[CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[CH:6]=[CH:7][C:8]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=3[N:10]([C:19](=[O:21])[CH3:20])[CH2:11][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)C=Cc1ccc(Br)cc1CN2
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)N1Cc2cc(Br)ccc2C=Cc2cc(Cl)ccc21
Yield: 71.7 %

Procedure:
To a mixture of 8-Bromo-2-chloro-5,6-dihydro-dibenzo[b,f]azocine (0.8 g, 2.5 mmole) in toluene (10 mL) was added acetic anhydride (1.2 mL, 12.5 mmole) and N,N-dimethylaminopyridine (1.51 g, 12.5 mmole). The reaction mixture was refluxed for 2 hours, concentrated and purified by flash chromatography over silica gel eluting with 30% ethyl acetate/hexane to give 1-(8-Bromo-2-chloro-6H-dibenzo[b,f]azocin-5-yl)-ethanone (0.65 g, 72%). 1HNMR (CDCl3) δ7.32 (d, 1H, J=1.76 Hz), 7.23 (dd, 1H, J=7.70, 1.76 Hz), 7.19 (m, 2H), 7.06 (d, 1H, J=8.80 Hz), 6.91 (d, 1H, J=8.36 Hz), 6.68 (d, 1H, J=13.16 Hz), 6.47 (d, 1H, J=12.76 Hz), 5.42 (d, 1H, J=14.96 Hz), 4.08 (d, 1H, J=15.36 Hz), 1.68 (s, 3H). HPLC Rt=4.05 min. m/z=362 (M+H+).