Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[C:22](=S)=[S:23].CCN=C=NCCCN(C)C.CCN(CC)CC>C1COCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:5]2[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([N:1]=[C:22]=[S:23])[N:8]=[C:7]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[C:6]=2[CH:15]=1
Reactant: S=C=S
Reactant: CN1C(=O)C(N)N=C(c2cccnc2)c2cc(Cl)ccc21
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1C(=O)C(N=C=S)N=C(c2cccnc2)c2cc(Cl)ccc21
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 42.1 %

Procedure:
As illustrated in the scheme above, a solution of 3-amino-7-chloro-1,3-dihydro-1-methyl-5-(3-pyridinyl)-2H-1,4benzodiazepin-2-one (1.36 g, 4.52 mmol) in dry THF (55 mL) was cooled to −15° C. Carbon disulfide (2.7 mL, 45 mmol) was added, followed by EDCI (1.73 g, 9.03 mmol). The mixture was stirred for 10 min., and then Et3N (1.26 mL, 9.04 mmol) was added. The reaction was stirred for 16 h while it was allowed to slowly warm to room temperature. The precipitated solid was removed by filtration and was washed well with CH2Cl2 and then discarded. The filtrate was concentrated in vacuo, and the residue was dissolved in CH2Cl2. The organic phase was washed with water, saturated NaHCO3, and brine, and was then dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude product by silica gel column chromatography (3:1 CH2Cl2:EtOAc) provided the title compound as a solid (0.652 g, 42%). 1H-NMR (CDCl3): δ 8.75 (s, 2H), 8.12 (dt, J=2.0 Hz, J=8.0 Hz, 1H), 7.63 (dd, J=2.0 Hz, J=8.8 Hz, 1H), 7.43 (dd, J=4.8 Hz, J=8.0 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 5.22 (s, 1H), 3.50 (s, 3H). MS (ESI) (M+H)+=343.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:7]([O:9]CC)=O.[CH2:16]([N:19]1[C:23]2[CH:24]=[C:25]([NH:29][C:30](OCC)=[O:31])[C:26]([F:28])=[CH:27][C:22]=2[N:21]=[C:20]1[C:35]([F:38])([F:37])[F:36])[C:17]#[CH:18].N12CCCN=C1CCCCC2.Cl>CN(C)C=O>[CH2:16]([N:19]1[C:23]2[CH:24]=[C:25]([N:29]3[C:7](=[O:9])[CH:6]=[C:5]([C:12]([F:13])([F:14])[F:15])[NH:4][C:30]3=[O:31])[C:26]([F:28])=[CH:27][C:22]=2[N:21]=[C:20]1[C:35]([F:37])([F:38])[F:36])[C:17]#[CH:18]
Reactant: C#CCn1c(C(F)(F)F)nc2cc(F)c(NC(=O)OCC)cc21
Reactant: CCOC(=O)C=C(N)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: C#CCn1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 0.4 gram (0.005 mole) of sodium methoxide in 5 mL of N,N-dimethylformamide was cooled to about 0°-5° C., and 1.8 grams (0.005 mole) of ethyl 3-amino-4,4,4-trifluoro-2-butenoate in 15 mL of N,N-dimethylformamide was added dropwise. Upon completion of the addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 30 minutes. After this time, the reaction mixture was again cooled, and a solution of 1.8 grams (0.005 mole) of 1-(2-propyn-1-yl)-2-trifluoromethyl-5-fluoro-6-ethoxycarbonylaminobenzimidazole in 20 mL of N,N-dimethylformamide was added dropwise. The reaction mixture was heated to 110° C., and 0.24 mL (catalyst) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added in one portion. Upon completion of the addition, the reaction mixture was heated to about 130° C., where it stirred for about 3.5 hours. The reaction mixture was then allowed to cool to ambient temperature as it stirred for about 72 hours, after which the reaction mixture was poured into ice-cold aqueous 3N hydrochloric acid. The resultant precipitate was collected by filtration and dried, yielding 0.6 gram of 3-[1-(2-propyn-1-yl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([O:23]C)[CH:17]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br>C(O)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([OH:23])[CH:17]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C2CCCN(CCCc3ccccc3)C2)ccc1F
Agent: Br
Solvent: CC(=O)O
Product: Oc1cc(C2CCCN(CCCc3ccccc3)C2)ccc1F
Yield: 32 %

Procedure:
The 1-(3-phenylpropyl)-3-(4-fluoro-3-methoxyphenyl)piperidine from Preparation 5 was reacted with 48% aqueous hydrobromic acid in glacial acetic acid using the procedure of Example 3. The product was chromatographed on silica gel, eluting with ethyl acetate/hexane/triethylamine (5:5:3). This afforded a 32% yield of the title compound, [alpha]D25 =-21.2° (c=1; C2H5OH).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:25]([CH:22]2[CH2:24][CH2:23]2)=[O:26])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cccnc2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CN(C(=O)C2CC2)c2cccnc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl)amine 17 (56 mg, 0.19 mmol) and piperidinomethyl polystyrene resin (3.5 mM/g, 60 mg) in 0.6 mL of dry CH2Cl2 was added cyclopropanecarbonyl chloride (98%, 21 μL, 1.2 eq.) at room temperature. After being shaken at room temperature overnight, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of CH2Cl2 afforded Cyclopropanecarboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl)amide 22 (50 mg, 73%). LRMS 260 (M-100)+.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[NH2:35][C:36]1[C:41]([N+:42]([O-])=O)=[C:40]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][C:52]([NH:54][C:55]3[S:56][CH:57]=[CH:58][N:59]=3)=[O:53])[CH2:47][CH2:46]2)[C:39]([Br:60])=[CH:38][N:37]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH:69]([CH:71]1[CH2:73][CH:72]1[C:74]([O:76][CH2:77][CH3:78])=[O:75])=O>C(O)C.CN(C=O)C>[Br:60][C:39]1[C:40]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][C:52](=[O:53])[NH:54][C:55]3[S:56][CH:57]=[CH:58][N:59]=3)[CH2:47][CH2:46]2)=[C:41]2[N:42]=[C:69]([CH:71]3[CH2:73][CH:72]3[C:74]([O:76][CH2:77][CH3:78])=[O:75])[NH:35][C:36]2=[N:37][CH:38]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: CCOC(=O)C1CC1C=O
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC1c1nc2c(N3CCN(CC(=O)Nc4nccs4)CC3)c(Br)cnc2[nH]1
Reaction time: 16 h
Yield: 25.4 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide (63 mg, 0.14 mmol), DMF (1.3 mL), ethanol (0.2 mL), 1M Na2S2O4 (3 eq, 0.43 mmol, 0.43 mL) and ethyl 2-formyl-1-cyclopropanecarboxylate (1.1 eq, 0.16 mmol, 0.021 mL). After 16 h, concentration in vacuo and preparation by preparative tlc (EtOAc—CH2Cl2-MeOH, 50:50:2) gave the product (19 mg, 25%) as a colourless solid; 1H-NMR (500 MHz, DMSO-d6) 1.21 (t, J=7.1 Hz, 3H, CH2CH3), 1.56 (app. quintet, J=4.6 Hz, 1H, cyclopropane CHAHB), 1.64-1.67 (m, 1H, cyclopropane CHAHB), 2.26 (app. quintet, J=5.0 Hz, cyclopropane CH), 2.73 (br s, 4H, piperazine N(CH2)2), 3.38 (s, 2H, NCH2CO), 3.57 (br s, 4H, piperazine N(CH2)2), 4.13 (q, J=7.1 Hz, 2H, CH2CH3), 7.23 (d, J=3.5 Hz, 1H, thiazole H-4 or H-5), 7.48 (d, J=3.5 Hz, 1H, thiazole H-4 or H-5), 8.17 (s, 1H, imidazo[4,5-b]pyridine H-5), 11.86 (br s, 1H, CONH or imidazo[4,5-b]pyridine NH), 12.94 (br s, 1H, CONH or imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[NH:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1C(O)=O>C1(C)C=CC=CC=1>[N:13]12[CH2:20][CH2:19][CH2:18][CH:14]1[CH2:3][CH:2]1[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]1
Reactant: C=CCN(CC=O)C(=O)OCC
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CC3CCCN3C2C1

Procedure:
8.6 g (50 mmol) of ethyl N-allyl-N-(2-oxoethyl)-carbamate are heated under reflux overnight with 5.8 g (50 mmol) of proline in 200 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>CO.[Pd]>[C:4]1([CH2:3][CH2:2][C:1]([O:11][CH2:12][CH3:13])=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C=Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccccc1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A 500 mL 3-necked round bottom flask was added a solution of ethyl cinnamate (10 g, 56.75 mmol) in methanol (200 mL). To the mixture was added Pd/C (2 g) followed by addition of hydrogen gas. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 35° C. in a bath of oil. A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 10 g (99%) of ethyl 3-phenylpropanoate as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5](Cl)=[O:6].[CH3:15][C:16]1[C:20]([CH2:21][N:22]2[CH2:26][CH2:25][C@@H:24]([NH:27][C:28](=[O:31])[CH2:29][NH2:30])[CH2:23]2)=[C:19]([CH3:32])[O:18][N:17]=1.CO>C(Cl)(Cl)Cl.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([NH:30][CH2:29][C:28]([NH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([CH2:21][C:20]2[C:16]([CH3:15])=[N:17][O:18][C:19]=2[CH3:32])[CH2:23]1)=[O:31])=[O:6]
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Reactant: Cc1noc(C)c1CN1CC[C@@H](NC(=O)CN)C1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1noc(C)c1CN1CC[C@@H](NC(=O)CNC(=O)c2cc(F)cc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A dichloromethane solution (1 mL) of 3-fluoro-5-(trifluoromethyl)benzoyl chloride (0.058 mmol) was added to a solution of (R)-1-(3,5-dimethylisoxazol-4-ylmethyl)-3-(glycylamino)pyrrolidine (0.050 mmol) and a piperidinomethylpolystyrene (58 mg) in chloroform (0.2 mL) and dichloromethane (0.75 ml). The reaction mixture was stirred at room temperature for 2 hours, and methanol (1.0 mL) was then added. The resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was loaded onto a Varian™ SCX column and washed with methanol (16 mL). The obtained crude product was eluted with a solution of 2 M NH3 in methanol (6 mL) and concentrated to provide (R)-3-[N-[3-fluoro-5-(trifluoromethyl)benzoyl]glycyl]amino-1-(3,5-dimethylisoxazol-4-ylmethyl)pyrrolidine (Compd. No. 1191) (19.5 mg, 88%). The purity was determined by RPLC/MS (100%). ESI/MS m/e 443.2 (M++H, C20H22F4N4O3).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=1)[NH2:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.O>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:26][NH:25][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=1
Reactant: Cc1ccc(NN)nc1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(NNC(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)nc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A 50-mL, 3-necked, round bottom flask, charged with a solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.25 g) in EtOAc (10 mL) was treated with 2-hydrazinyl-5-methylpyridine (0.97 g, 1.1 eq.). The mixture was cooled to −60° C. and treated with T3P (propyl phosphonic anhydride; 0.85 mL, 2.0 eq.) and DIPEA (0.5 mL, 4.0 eq.). The mixture was stirred for 30 min then poured into water (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg) to afford a crude compound that was purified by column chromatography (SiO2, 60/120 mesh, MeOH:CH2Cl2 as mobile phase). The desired compound started eluting with 2.5% MeOH:CH2Cl2. Fractions containing the desired compound were combined and concentrated under reduced pressure to afford 0.130 g (yield: 40%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(5-methylpyridin-2-yl)acrylohydrazide. 1H NMR (400 MHz, CDCl3) δ, 10.38 (s, exchangeable, 1H), 9.65 (s, 1H), 8.54 (s, 2H), 8.40 (s, exchangeable, 1H), 8.29 (s, 1H), 7.90 (s, 1H), 7.48-7.51 (d, J=10.4 Hz, 1H), 7.33-7.36 (dd, J=2 Hz, J=6 Hz, 1H), 6.61-6.63 (d, J=8.4 Hz, 1H), 6.20-6.23 (d, J=10.4 Hz, 1H), 2.15 (s, 3H); LCMS for C19H15F6N6O [M+H]+ 457.35; found 457.24 (RT 2.61 min, purity: 99.13%).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8](=[NH:10])[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:46][C:47]1[CH:48]=[CH:49][C:50]([O:56][CH3:57])=[C:51]([CH:55]=1)[C:52](O)=[O:53]>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[O:9][C:8](=[N:10][C:52](=[O:53])[C:51]2[CH:55]=[C:47]([Cl:46])[CH:48]=[CH:49][C:50]=2[O:56][CH3:57])[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)c(=N)o1
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)N=c1oc(C(C)(C)C)cn1C[C@H]1CCCO1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of Example 13B (1.24 g, 5.53 mmol) in tetrahydrofuran (10 mL) was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1.06 g, 5.53 mmol), 1-hydroxybenzotriazole (0.85 g, 5.55 mmol), triethylamine (0.45 mL, 3.2 mmol) and 5-chloro-2-methoxybenzoic acid (Aldrich) (1.03 g, 5.55 mmol). The mixture was stirred at 80° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with 1 M aqueous NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to provide the title product. MS (ESI+) m/z 393 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 1.20 (s, 9H), 1.59-1.71 (m, 1H), 1.83-1.97 (m, 2H), 2.02-2.14 (m, 1H), 3.66 (dd, J=14.2, 7.5 Hz, 1H), 3.75-3.82 (m, 1H), 3.82 (s, 3H), 3.82-3.92 (m, 1H), 4.07 (dd, J=14.2, 2.7 Hz, 1H), 4.13-4.24 (m, 1H), 6.52 (s, 1H), 6.83 (d, J=8.8 Hz, 1H), 7.27 (dd, J=9.0, 2.7 Hz, 1H), 7.74 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([N:8]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]4[N:20](S(C5C=CC(C)=CC=5)(=O)=O)[CH:19]=[CH:18][C:16]4=3)[CH2:11][CH2:10][CH2:9]2)[CH2:6][C@@H:5]([NH:31][S:32]([CH:35]2[CH2:37][CH2:36]2)(=[O:34])=[O:33])[CH2:4]1)[CH3:2].[OH-].[Na+].O.CCOC(C)=O>O1CCOCC1>[CH2:1]([C@H:3]1[C@@H:7]([N:8]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]4[NH:20][CH:19]=[CH:18][C:16]4=3)[CH2:11][CH2:10][CH2:9]2)[CH2:6][C@@H:5]([NH:31][S:32]([CH:35]2[CH2:36][CH2:37]2)(=[O:34])=[O:33])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1N1CCCc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1N1CCCc2cnc3[nH]ccc3c21
Temperature: 80 °C
Yield: 67.7 %

Procedure:
To a solution of N-((1S,3R,4S)-3-ethyl-4-(7-tosyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.041 g, 0.076 mmol) in 1,4-dioxane was added aqueous NaOH (5 N, 0.106 mL, 0.529 mmol). The reaction was heated to about 80° C. for about 16 h. The reaction mixture was cooled to ambient temperature and water (5 mL) and EtOAc (10 mL) were added. The layers were separated and the aqueous phase was extracted with EtOAc (2×10 mL). The combined organics were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to give N-((1S,3R,4S)-3-ethyl-4-(2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridin-1-yl)cyclopentyl)cyclopropane-sulfonamide (0.02 g, 72%) as a white solid: LC/MS (Table 1, Method a) Rt=1.48 min; MS m/z: 389 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=O.[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][CH3:13])=[CH:6][C:3]=1[CH2:4][NH:18][CH2:17][CH:14]1[CH2:16][CH2:15]1
Reactant: COCCc1ccc(Cl)c(C=O)c1
Reactant: NCC1CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCc1ccc(Cl)c(CNCC2CC2)c1
Temperature: 70 °C

Procedure:
To a solution of 2-chloro-5-(2-methoxyethyl)benzaldehyde from Amine 7, Step 6 (1 eq.) in methanol (0.8 M) was added 1-cyclopropylmethanamine (1.2 eq.) and sodium bicarbonate (1.5 eq). The vessel was sealed and heated at 70° C. for 2 h. The insolubles were removed via filtration and to the filtrate was then added sodium borohydride (1.5 eq.) at 0° C. The reaction mixture was allowed to warm slowly to RT overnight. The volatiles were removed in vacuo and the resulting residue was partitioned between 1 N aq. NaOH and ether. The aqueous layer was separated and back extracted with ether. The combined ethereal extracts were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[C:5]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[CH:7]3[CH2:8][N:9]=[CH:10][C:11]([CH:12]=1)=[C:6]23.[CH2:23]([Br:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C[Mg]I>>[Br-:30].[CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[C:5]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[CH:7]3[CH2:8][N+:9]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:10][C:11]([CH:12]=1)=[C:6]23
Reactant: COc1cc2c3c(c1OC)CCc1ccccc1C3CN=C2
Reactant: BrCc1ccccc1
Agent: C[Mg]I
Product: COc1cc2c3c(c1OC)CCc1ccccc1C3C[N+](Cc1ccccc1)=C2
Product: [Br-]

Procedure:
By following serially the procedure of step (a) of example 5 and the procedure of example 6 and selecting 5,6-dimethoxy-1,7,8,12b-tetrahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinoline as the starting material of formula II, benzyl bromide as the organohalide and methyl magnesium iodide as the Grignard reagent, (3,12b-trans)-5,6-dimethoxy-3-methyl-2-(phenylmethyl)-1,2,3,7,8,12b-hexahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinoline, mp 160°-162° C., NMR (CDCl3) δ6.5 (s, 1H), 7.25 (m, 9H), was obtained via 5,6-dimethoxy-2-phenylmethyl-1,7,8,12b-tetrahydrobenzo-[6,7]cyclohepta[1,2,3-de]isoquinolinium bromide, mp 196° C. (dec), NMR (DMSO-d6) δ 3.85 & 3.95 (2s, 6H), 5.15 (m, 1H), 5.32 & 5.62 (2d, J=13.7 Hz, 2H), 6.1-7.8 (m, 10H), 9.6 (s, 1H).
Reaction SMILES: C(=N[OH:9])C1C=CC=CC=1.CN(C=O)C.[H-].[Na+].O1CCOCC1.[C:23]([C:25]([C:28]1[C:33]([C:34]#[C:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][CH:31]=[CH:30][N:29]=1)([CH3:27])[CH3:26])#[N:24]>>[OH:9][C:34]1[C:33]2[CH:32]=[CH:31][CH:30]=[N:29][C:28]=2[C:25]([CH3:27])([CH3:26])[C:23](=[NH:24])[C:35]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: ON=Cc1ccccc1
Reactant: CCOC(=O)C#Cc1cccnc1C(C)(C)C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(O)c2cccnc2C(C)(C)C1=N
Reaction time: 0.5 h

Procedure:
A solution of benzaldehyde oxime (0.6 g, 5 mmol) in dry DMF (10 mL, 129 mmol) was added to a stirred suspension of 60% NaH (0.2 g, 5 mmol) in dry 1,4-dioxane (10 mL, 117 mmol) under a nitrogen atmosphere at room temperature. After 0.5 hours, a solution of the ethyl 3-(2-(2-cyanopropan-2-yl)pyridin-3-yl)propiolate (0.98 g, 4 mmol) in dry DMF (10 mL, 129 mmol) was added, and the solution was stirred for 30 minutes. The solvent was removed under vacuum, and water was added to the residue. The product was extracted with EtOAc. The organic layer was washed with water (3×) and then with saturated NH4Cl and brine (3× each) and dried over MgSO4. The resulting mixture was concentrated in vacuo to give a light-yellow crystalline solid/yellow oil. The yellow residue was washed with hexane providing the product as a yellow solid which was filtered off (0.65 g, 62%). MS (m/z)=261 (M+H)+. Calculated for C14H16N2O3 260.3.
Reaction SMILES: [C:1]([OH:4])(=O)C.ClC1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:14][CH2:13]2)[N:9]=[CH:8][N:7]=1.C([O-])(=O)C.[Na+]>O>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH2:16][CH2:17][N:12]([C:10]3[N:9]=[CH:8][NH:7][C:1](=[O:4])[N:11]=3)[CH2:13][CH:14]=2)=[CH:23][CH:22]=1
Reactant: CC(=O)O
Reactant: Fc1ccc(C2=CCN(c3ncnc(Cl)n3)CC2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=c1nc(N2CC=C(c3ccc(F)cc3)CC2)nc[nH]1
Temperature: 0 °C
Yield: 89 %

Procedure:
To an acetic acid (9.0 mL)-water (1.8 mL) solution of 2-chloro-4-[4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl]-1,3,5-triazine (900 mg, 3.10 mmol) synthesized in Reference Synthesis Example 341, sodium acetate (900 mg, 11.0 mmol) was added and the resultant mixture was stirred at 90° C. for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure and water was added to the obtained residue, followed by stirring the resultant mixture at 0° C. The precipitated solid was collected by filtration and the solid was dried under reduced pressure to obtain the title compound (750 mg, yield 89%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:7]=[C:8]([C:12]([F:24])([F:23])[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)([F:15])[F:14])[CH:9]=[CH:10][CH:11]=1.[C:25](=O)=[O:26]>ClC1C=CC=CC=1>[N:22]([C:18]1[CH:17]=[C:16]([C:13]([F:14])([F:15])[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([N:5]=[C:1]=[O:2])[CH:7]=2)([F:23])[F:24])[CH:21]=[CH:20][CH:19]=1)=[C:25]=[O:26]
Reactant: Nc1cccc(C(F)(F)C(F)(F)c2cccc(N)c2)c1
Reactant: O=C=O
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C=Nc1cccc(C(F)(F)C(F)(F)c2cccc(N=C=O)c2)c1
Temperature: 120 °C

Procedure:
621 g of phosgene are condensed in 2.3 l of chlorobenzene at about 0° C. 353 g of 1,2-bis(3-aminophenyl)-1,1,2,2-tetrafluoroethane, dissolved in 1.2 l of chlorobenzene, are slowly added at a temperature of -10° C. to +10° C. The batch is heated up to 120° C. in the course of four hours. Further gaseous phosgene is passed in from about 80° C. The solution becomes clear at 100° to 110° C. Phosgene is passed through the solution at 120° C. for a further 90 minutes. The phosgene still dissolved is then blown out with CO2 and the mixture is subsequently worked up by distillation. 355 g of 1,2-bis-(3-isocyanatophenyl)-1,1,2,2-tetrafluoroethane, boiling point: 145° to 150° C./0.1 mbar, melting point: 139° to 140° C. (purity, according to gas chromatography, 97%) are obtained.
Reaction SMILES: [C:1]([CH2:3][C:4](OCC)=O)#[N:2].[NH2:9][C:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=1>>[N:16]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:4]=1[CH2:3][C:1]#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: Nc1cccnc1N
Product: N#CCc1nc2cccnc2[nH]1
Temperature: 25 °C

Procedure:
Ethyl cyanoacetate (1.5 eq) and 2,3-diaminopyridine (1 eq) were heated at 185° C. for 30 minutes. The reaction mixture was cooled to room temperature and the black solid was triturated with ether. The desired product was thus obtained as a dark brown powder. LC/MS m/z 159.1 (MH+), Rt 0.44 minutes.