Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:4]([F:20])[CH:3]=1.O[CH:22]([C:28](C)=C)[C:23](OCC)=O.Cl.C[OH:33]>C(N(CCCC)CCCC)CCC>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:18](=[O:33])[C:17](=[C:22]([CH3:28])[CH3:23])[O:16][C:15]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: C=C(C)C(O)C(=O)OCC
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CO
Agent: Cl
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 200 °C
Reaction time: 3.5 h
Yield: 67.4 %

Procedure:
Ethyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate (6.02 g, 20 mmol), ferric chloride (53.5 mg, 0.33 mmol) and tributylamine (185 mg, 1.00 -mmol) were introduced into a two-necked flask (50 cc) equipped with a distillation unit and heated to 200° C. Ethyl 2-hydroxy-3-methyl-3-butenoate (4.33 g, 30 mmol) was added dropwise to the mixed solution over 30 minutes, and after the addition, the solution was stirred at 200° C. for 3.5 hours. After completion of the reaction, the reaction solution was allowed to cool to 70 to 80° C., and a mixed solution consisting of methanol (10 mL) and 6N hydrochloric acid (0.5 mL) was added thereto and mixed homogeneously. Then, the reaction solution was left to stand at room temperature. The precipitated solid was collected by filtration, washed with a mixed solution consisting of methanol (20 mL) and 6N hydrochloric acid (1 mL) and then water (20 mL) and dried completely under reduced pressure to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (4.77 g, yield 67.4%).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=O)[CH:2]=1.[C:16]([O:20][C:21](=[O:31])[NH:22][CH2:23][CH2:24][N:25]1[CH:29]=[C:28]([NH2:30])[CH:27]=[N:26]1)([CH3:19])([CH3:18])[CH3:17].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[C:16]([O:20][C:21](=[O:31])[NH:22][CH2:23][CH2:24][N:25]1[CH:29]=[C:28]([NH:30][C:12]([C:8]2[N:9]=[CH:10][O:11][C:7]=2[C:3]2[CH:2]=[C:1]([CH3:15])[CH:6]=[CH:5][CH:4]=2)=[O:14])[CH:27]=[N:26]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC(C)(C)OC(=O)NCCn1cc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCNC(=O)OC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(m-tolyl)oxazole-4-carboxylic acid (1.60 g, 7.87 mmol) in DCM (15 mL), tert-butyl(2-(4-amino-1H-pyrazol-1-yl)ethyl)carbamate (1.80 g, 7.96 mmol), DIPEA (6.8 mL, 39.86 mmol) and HATU (7.485 g, 19.69 mmol) was added. After stirring the reaction mixture at rt for 18 h, the reaction mixture was diluted with DCM and H2O. The org. layer was separated and the aq. layer was extracted with DCM (3×). The combined org. layers wered dried (MgSO4), filtered and the solvent was removed under reduced pressure. Purification by FC (EtOA/hex 3:7 to 1:1) yielded tert-butyl(2-(4-(5-(m-tolyl)oxazole-4-carboxamido)-1H-pyrazol-1-yl)ethyl)carbamate as a white solid. LC-MS conditions B: tR=0.8 min, [M+H]+=412.46.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:41]([O:45][CH:46](Cl)[CH3:47])(=[O:44])[CH2:42][CH3:43]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CCOC(C)=O>[C:41]([O:45][CH:46]([N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)[CH3:47])(=[O:44])[CH2:42][CH3:43]
Reactant: CCC(=O)OC(C)Cl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(C)OC(=O)CC)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 58.3 %

Procedure:
To a solution of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.2 g, 0.41 mmol) in DMF (1 mL) was added Et3N (165 mg, 1.64 mmol). The reaction was stirred at 10° C. for 10 min, followed by the dropwise addition of a solution of TBAB (264 mg, 1.64 mmol) in DMF (0.5 mL) and a solution of 1-chloroethyl propionate (67 mg, 0.41 mmol) in DMF (0.5 mL) over 30 min. The mixture was stirred at 10° C. for another 3 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1) to afford the title compound as a white solid (141 mg, 58%). The title compound was characterized by LCMS and 1H NMR as shown below:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=1>C(O)CCC.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>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([S:32][C:29]4[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=4)[CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Br)cc23)CC1
Reactant: Sc1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Sc4ccc(Cl)cc4)cc23)CC1
Temperature: 110 °C
Yield: 50.6 %

Procedure:
A mixture of 4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), p-chloro-thiophenol (188 mg, 1.3 mmol), NatBuO (0.44 g, 4.5 mmol), Pd(PPh3)4 (74 mg, 0.065 mmol) in nBuOH (10 mL) was heated at 110° C., 3 h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL×3), separated and dried (MgSO4), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiO2, n-pentane:ethyl acetate 9.5:0.5→8:2) to give 300 mg of the title compound as colourless oil (yield 50%). 1H NMR (CDCl3) δ 8.05-8.15 (m, 2H), 7.60-7.70 (m, 2H), 7.40-7.50 (m, 2H), 7.15-7.30 (m, 3H), 3.45-3.55 (m, 4H), 3.10-3.15 (m, 4H), 1.50 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C.O>[CH2:19]([NH:1][C:2]1[C:3]([F:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccc2c(c1F)CCC2=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: O=C1CCc2c1ccc(NCc1ccccc1)c2F
Yield: 10.4 %

Procedure:
As presented in the following reaction formula, a mixture of 5-amino-4-fluoro-2,3-dihydro-1H-inden-1-one (2.3 g, 14 mmol), cesium carbonate (Cs2CO3; 12 g, 28 mmol) and benzyl bromide (0.17 g, 72 mmol) in acetonitrile (CH3CN; 20 mL) was stirred under reflux for 48 hours. The mixture was concentrated to obtain the residue, which was dissolved in water (20 mL). The resulting solution was extracted three times with 20 mL of ethyl acetate. The combined organic phase was washed with saturated brine (50 mL), and dried and concentrated with anhydrous sodium sulfate to thereby give a crude product, which was purified by pre-TLC to give 5-(benzylamino)-4-fluoro-2,3-dihydro-1H-inden-1-one (370 mg, yield: 10%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.N1C2C=CC(C#N)=CC=2N[CH:17]=1.NC1C=CC(C#N)=CC=1[N+]([O-])=O>>[F:13][C:12]([F:15])([F:14])[O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[CH:17][NH:1][C:4]=2[CH:10]=1
Reactant: N#Cc1ccc2nc[nH]c2c1
Reactant: Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Agent: N#Cc1ccc(N)c([N+](=O)[O-])c1
Product: FC(F)(F)Oc1ccc2nc[nH]c2c1

Procedure:
6-(trifluoromethoxy)-1H-benzo[d]imidazole (4) was prepared in two steps from 2-nitro-4-(trifluoromethoxy)aniline (5) using procedures identical to those used to make 3H-benzo[d]imidazole-5-carbonitrile (3) from 4-amino-3-nitrobenzonitrile (1, examples 1, 2).
Reaction SMILES: F[C@@H:2]1[CH2:6][N:5]([C:7](OC(C)(C)C)=O)[C@H:4]([C:14](=[O:24])[NH:15][C@@H:16]2[C@@H:23]3[C@@H:19]([CH2:20][NH:21][CH2:22]3)[CH2:18][CH2:17]2)[CH2:3]1.Br[C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1.Br[C:37]1C=C(C(F)(F)F)C=CN=1>>[CH3:7][NH:5][C@H:4]([C:14]([NH:15][C@@H:16]1[C@@H:23]2[C@@H:19]([CH2:20][N:21]([C:26]3[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=3)[CH2:22]2)[CH2:18][CH2:17]1)=[O:24])[CH2:3][CH:2]([CH3:6])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21
Reactant: FC(F)(F)c1ccnc(Br)c1
Reactant: FC(F)(F)c1ccnc(Br)n1
Product: CN[C@@H](CC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3nccc(C(F)(F)F)n3)C[C@@H]21

Procedure:
The title compound was prepared by substituting tert-butyl methyl((S)-4-methyl-1-((3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylamino)-1-oxopentan-2-yl)carbamate from Example 619 Step 1 for (2S,4S)-tert-butyl 4-fluoro-2-((3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)pyrrolidine-1-carboxylate and 2-bromo-4-(trifluoromethyl)pyrimidine for 2-bromo-4-(trifluoromethyl)pyridine in the procedure described in Example 637: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.49 (d, J=4.8, 1H), 7.75-7.64 (m, 1H), 6.74 (d, J=4.8, 1H), 4.29 (dt, J=14.2, 7.2, 1H), 3.83 (d, J=4.5, 1H), 3.75 (dd, J=11.9, 8.2, 1H), 3.46 (dd, J=11.9, 4.8, 1H), 3.17-3.09 (m, 1H), 2.83-2.65 (m, 2H), 2.38 (s, 3H), 2.19-2.09 (m, 1H), 2.01-1.89 (m, 1H), 1.84 (dq, J=13.1, 6.6, 1H), 1.73-1.60 (m, 2H), 1.56-1.37 (m, 2H), 0.93 (d, J=6.6, 3H), 0.89 (d, J=6.6, 3H); MS (ESI+) m/z 400 (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][N:10]([C:25]3[C:26]4[C@H:33]([CH3:34])[CH2:32][CH2:31][C:27]=4[N:28]=[CH:29][N:30]=3)[C:7]2=[CH:8][CH:9]=1.[C:35]1(=[O:45])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:44])[NH:36]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:45]=[C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:44])[N:36]1[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]3)[CH2:11][N:10]([C:25]3[C:26]4[C@H:33]([CH3:34])[CH2:32][CH2:31][C:27]=4[N:28]=[CH:29][N:30]=3)[C:7]2=[CH:8][CH:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(CCO)ccc43)c21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(CCN5C(=O)c6ccccc6C5=O)ccc43)c21
Temperature: 0 °C
Yield: 52.4 %

Procedure:
To a solution of (R)-tert-butyl 5-(2-hydroxyethyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.021 g, 0.045 mmol) in THF (0.2 mL) was added isoindoline-1,3-dione (0.020 g, 0.14 mmol) and PS—PPh3 (0.081 g, 0.14 mmol). The solution was cooled to 0° C. and DEAD (0.021 ml, 0.14 mmol) was added dropwise. The reaction was allowed to stir with warming to about room temperature for 2 hours. The reaction was filtered and the solvent was evaporated. The crude residue was purified by column chromatography (1-3% MeOH/DCM) to yield (R)-tert-butyl 5-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.014 g, 52%). LCMS (APCI+) m/z 594 [M+H]+; Rt=4.15 min.
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.O[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[SH:27][C:28]1[N:29](C)[CH:30]=[CH:31][N:32]=1>>[CH3:1][CH:9]([S:27][C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Reactant: Cn1ccnc1S
Reactant: O=C(O)C(F)(F)F
Product: CC(Sc1ncc[nH]1)c1ccc(OC(=O)N(C)c2ccccc2)cc1
Yield: 22 %

Procedure:
The title compound was prepared as its TFA salt in 22% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 2-mercapto-1-methylimidazole. 1H NMR (400 MHz; CDCl3): δ 3.34 (s, 3H), 3.40 (br s, 3H), 4.30 (s, 2H), 6.98 (br s, 2H), 7.08-7.11 (m, 3H), 7.27-7.42 (m, 5H), 7.48 (d, 1H); HPLC-MS: m/z=354.1 (M+1); Rt=2.12 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24][C:25](O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18]2.Cl[C:29]1C=CC(C2CCNCC2)=CC=1>>[CH3:29][N:15]1[C:16]([CH2:23][CH2:24][CH2:25][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[C:17]2[C:22]([CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:14]1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: Clc1ccc(C2CCNCC2)cc1
Product: Cc1ccc(N2CCN(CCCc3c4c(nn3C)CCCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 9 and 1-(4-methylphenyl)piperazine are used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 4,5,6,7-tetrahydro-2-methyl-3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)-2H-indazole is obtained.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[CH3:13].C(O)(=O)C>C(O)C.O.[Fe]>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:14])=[C:5]([CH3:13])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1OC(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1cc(N)ccc1OC(F)F
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a solution of 1-(difluoromethoxy)-2-methyl-4-nitrobenzene (10 g, 48.28 mmol) in ethanol (150 mL) and water (150 mL) was added iron powder (12 g, 214.29 mmol). Acetic acid (cat. amount) was added dropwise with stirring and the reaction mixture was heated at reflux for 20 minutes. The mixture was cooled to room temperature and solids were removed by filtration. Volatiles were removed in vacuo and the aqueous solution was extracted with EtOAc (3×150 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide 8 g (95%) of 4-amino-1-difluoromethoxy-2-methyl-benzene.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32].C(OCC)C>C(Cl)Cl.C(#N)C>[ClH:32].[NH:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][N:23]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1

Procedure:
4-[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester (1.35 g, 3.11 mmol) from Step 4 was dissolved in CH2Cl2 (30 mL) and treated with HCl in diethyl ether (10 mL, 2.0 M, 20 mmol). After 16 hours the reaction was concentrated in vacuo to form a residue and the residue was suspended in acetonitrile (10 mL) to yield a solid. Filtration of the solid provided the title compound as a white solid (1.1 g). 1H NMR (400 MHz, CD3OD) δ ppm 2.62 (td, J=6.11, 0.91 Hz, 2H) 2.67-2.81 (m, 2H) 3.14-3.21 (m, 2H) 3.22-3.29 (m, 2H) 6.56 (s, 1H) 6.99-7.09 (m, 2H) 7.10-7.18 (m, 2H) 7.42 (t, J=7.91 Hz, 1H) 8.09 (ddd, J=8.74, 2.60, 0.33 Hz, 1H) 8.41 (td, J=1.63, 0.74 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([N+:13]([O-])=O)[C@H:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[H][H].[Ni]>[NH3:8].[CH2:1]([N:8]1[CH2:9][C@@H:10]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C@H:11]([NH2:13])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([C@@H]2CN(Cc3ccccc3)C[C@H]2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COc1ccc([C@@H]2CN(Cc3ccccc3)C[C@H]2N)cc1
Product: N
Reaction time: 2 h
Yield: 124.5 %

Procedure:
trans-1-Benzyl-3-(4-methoxyphenyl)-4-nitropyrrolidine (0.205 g, 0.66 mmol) was dissolved in methanol (10 mL) and hydrogenated under a hydrogen atmosphere at atmospheric pressure in the presence of Raney nickel (˜8 mL). After stirring for 2 h the solution was concentrated in vacuo and purified by ion exchange chromatography on SCX-2 (solute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol to give the title compound (0.116 g, 62%) as a colourless oil that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:17](=[O:32])[N:18]=[C:19]2[NH:30][NH2:31])=[N:14]1.[N:37]#[C:38]Br>O1CCOCC1>[NH2:37][C:38]1[N:18]2[C:17](=[O:32])[N:16]([CH2:33][CH:34]3[CH2:35][CH2:36]3)[C:15]3[C:20](=[C:21]([C:22]4[N:26]([CH3:27])[CH:25]=[C:24]([C:28]#[N:29])[CH:23]=4)[N:13]([CH2:12][C:5]4[C:4]5[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=5)[N:8]=[CH:7][CH:6]=4)[N:14]=3)[C:19]2=[N:30][N:31]=1
Reactant: N#CBr
Reactant: Cn1cc(C#N)cc1-c1c2c(NN)nc(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Solvent: C1COCCO1
Product: Cn1cc(C#N)cc1-c1c2c(nn1Cc1ccnc3ccc(Cl)cc13)n(CC1CC1)c(=O)n1c(N)nnc21
Temperature: 100 °C

Procedure:
To a solution of 5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-4-hydrazino-6-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile (0.13 g) in dioxane (3 mL) was added cyanogen bromide (0.15 mL). The reaction was heated by microwave at 100° C. for 5 min. The mixture was concentrated and purified by HPLC yielding 27 mg of yellow foam, 1H NMR (300 MHz, CHLOROFORM-D) d ppm 0.56 (m, 4 H) 1.44 (m, 1H) 3.7 (s, 3H) 3.94 (m, 2H) 5.84 (m, 2H) 6.54 (d, 1H) 6.86 (m, 1H) 7.71 (m, 2H) 7.87 (m, 1H) 8.12 (m, 1H) 8.85 (m, 1H); ES M+H+=525.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]#[CH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]#[C:11][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:15][CH:16]=1)([CH3:5])([CH3:6])[CH3:7]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC#CC(=O)c1ccc(C(F)(F)F)cc1
Yield: 37.5 %

Procedure:
To a solution of N-boc-propargylamine (5.0 g, 32.2 mmol) in THF (100 mL) was added 4-trifluoromethylbenzoyl chloride (4.3 mL, 29.3 mmol), PdCl2(PPh3)2 (0.18 g, 0.264 mmol), and CuI (0.17 g, 0.879 mmol). The mixture was allowed to stir for 5 min at rt, at which time freshly distilled triethylamine (5.1 mL, 36.6 mmol) was added. After 30 min the resulting mixture was filtered, concentrated, and purified by flash column chromatography, or FCC, to afford the title compound as a colorless solid (3.6 g, 35%). MS (ESI): mass calcd. for C16H16F3NO3, 327.1; m/z found, 328.2 [M+H]+. 1H NMR (500 MHz, (DMSO) δ 8.26 (d, J=8.04 Hz, 2H), 7.96 (d, J=8.12 Hz, 2H), 7.62-7.54 (m, 1H), 4.14 (d, J=5.53 Hz, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][C:2](O)=O.C=O.[CH3:7][NH:8][CH3:9].[CH3:10][C:11]1[NH:12][C:13]2[C:18](C=1)=[CH:17][CH:16]=[CH:15][CH:14]=2>O1CCOCC1.O>[CH3:10][C:11]1[NH:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:2]=1[CH2:1][N:8]([CH3:9])[CH3:7]
Reactant: CC(=O)O
Reactant: Cc1cc2ccccc2[nH]1
Reactant: CNC
Agent: C=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1[nH]c2ccccc2c1CN(C)C

Procedure:
AcOH, 236 ml., was mixed with cooling and stirring with 62 ml. of 37% formaldehyde at 10°, and 154 ml of 25% aqueous dimethylamine was added dropwise with cooling so as to maintain the temperature at 10°. A solution of 100 g of 2-methylindole in 160 ml of dioxane was then added dropwise with cooling, again maintaining the temperature at 10°. The mixture was stirred at ice temperature for 1 hour and then overnight at room temperature. The mixture was then poured into 2.0 of water with stirring. A small amount of insoluble material was removed by filtration. The filtrate was treated with activated charcoal, filtered again, and the filtrate cooled and basified by the dropwise addition of about 225 ml. of 50% aqueous sodium hydroxide. The product was collected by filtration, washed with water, and air dried, yield 96 g. This material was dissoved in 700 ml of dilute aqueous HCl, treated with activated carbon, filtered, and again basified after diluting to 2 1. with water.The product was collected, air dried, and recrystallized from acetonitrile, yield 72 g., m.p. 117°-119°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.Cl.[CH2:11]([O:18][C:19](=[O:23])[CH2:20][NH:21][CH3:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19](=[O:23])[CH2:20][N:21]([C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([Cl:1])[N:7]=1)[CH3:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNCC(=O)OCc1ccccc1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: Cl
Product: Cc1cc(N(C)CC(=O)OCc2ccccc2)nc(Cl)n1
Yield: 62 %

Procedure:
Prepared in analogy to example 98a), using 2,4-dichloro-6-methylpyrimidine and sarcosine-benzylester hydrochloride. The title compound was isolated as a slightly yellow oil in a yield of 62%. MS ISP (m/e): 306.1 & 308.2 (100 & 38) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.40-7.35 (m, 5H), 6.23 (s broad, 1H), 5.19 (s, 2H), 4.39 (s broad, 2H), 3.11 (s broad, 3H), 2.36 (s, 3H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:16][C:15](=O)[C:14]3=[CH:18][C:19]([CH3:21])=[CH:20][N:13]3[CH2:12][C:11]=2[CH:22]=1>C(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]=[C:15]([Cl:3])[C:14]3=[CH:18][C:19]([CH3:21])=[CH:20][N:13]3[CH2:12][C:11]=2[CH:22]=1
Reactant: Cc1cc2n(c1)Cc1cc(Cl)ccc1NC2=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2n(c1)Cc1cc(Cl)ccc1N=C2Cl
Temperature: 25 °C
Yield: 97.2 %

Procedure:
Add phosphoryl chloride (1.47 mL, 2.43 g, 15.85 mmoles) to 7-chloro-2-methyl-5,10-dihydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one (1.117 g, 4.53 mmoles) in DCM (50 mL) and stir at room temperature over a weekend. Add ice water to the reaction mixture then add DCM, separate the aqueous layer and wash the DCM layer with water and sodium hydrogen carbonate solution. Dry the DCM solution with MgSO4, filter and evaporate the solvent in vacuo to give 7,11-dichloro-2-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.167 g).