Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:22])[C:9]([CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]=[O:21])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>C1COCC1>[C:23]1([CH:20]([C@@H:16]2[CH2:17][CH2:18][CH2:19][N:15]2[C:13](=[O:14])[CH2:12][CH2:11][C:9](=[O:10])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:22])[OH:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of (2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-al (200 mg) in THF (5 ml) was cooled to -25° C. A solution of phenyl magnesium bromide in THF (2M, 0.49 ml) was added dropwise to the solution. The reaction solution was stirred for 30 mins, at the same temperature, and for 30 mins at 0° C. A saturated aq. solution of ammonium chloride was added to the reaction solution. The mixture was extracted with EtOAc. The extract was washed, dried, and evaporated. The residue was purified by column chromatography on silica gel (EtOAc-CH3OH) to give the title compound (45 mg) having the following physical data:
Reaction SMILES: [C:1]12([CH2:11][C:12]([OH:14])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)([Cl:17])=O>>[C:1]12([CH2:11][C:12]([Cl:17])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Product: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
A solution of 1-adamantaneacetic acid (4.5 g) in thionyl chloride (20 ml) was heated at reflux temperature for 24 hours and then allowed to cool to ambient temperature. The excess thionyl chloride was removed under reduced pressure to leave the sub-title compound as a syrup (4.9 g).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=1.C1C(=O)N([I:19])C(=O)C1>>[F:11][C:2]([F:1])([F:10])[C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[I:19]
Reactant: Nc1cccc(C(F)(F)F)n1
Reactant: O=C1CCC(=O)N1I
Product: Nc1ccc(I)c(C(F)(F)F)n1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 4.8 g (30 mmol) 6-trifluoromethyl-pyridin-2-ylamine and 6.7 g (30 mmol) NIS. Yield after precipitation from the reaction mixture and isolation of additional product from the mother liquid by chromatography in silica gel: 5.73 g (67%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[O:13])[CH2:11][C:4]=2[CH:3]=1.C(O)(=O)/C=C\C(O)=O.ClC1[N:38]=[N:37]C2CCNCC=2C=1.C1C2C(=CC=CC=2)C=CC=1C(Cl)=O>C(O)C>[NH:37]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[O:13])[CH2:11][C:4]=2[CH:3]=1)[NH2:38]
Reactant: O=C(c1ccc2ccccc2c1)N1CCc2nnc(Cl)cc2C1
Reactant: Clc1cc2c(nn1)CCNC2
Agent: O=C(Cl)c1ccc2ccccc2c1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: NNc1cc2c(nn1)CCN(C(=O)c1ccc3ccccc3c1)C2

Procedure:
The 3-chloro-6-(2-naphthoyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, required as starting material, is produced in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and 2-naphthoyl chloride. Reaction time 22 hours at room temperature. M.P. 167°-170°(decomp., from 95% ethanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([CH:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.C(Cl)Cl>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)([CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[OH:9])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Yield: 91.8 %

Procedure:
A solution of 31.2 g (0.079 mole) of α,α-bis-(4-fluorophenyl)-1-(phenylmethyl)-4-piperidinemethanol in 400 ml of absolute ethanol was hydrogenated at 50 psi and 70° C. over 5% palladium-on-carbon over the weekend. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a gum as residue. Methylene chloride was added to the residue and the gum crystallized. The mixture was diluted with petroleum ether and the solid was collected by filtration, washed with petroleum ether and dried to yield 22 g (99%) of white solid which was recrystallized from isopropyl ether and 2-propanol, m.p. 159.5°-160.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][N:12]=1.C(OCC)(=O)C.[H][H]>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:13][N:12]=1
Reactant: [H][H]
Reactant: O=S(=O)(c1ccccc1)c1ccc(/C=C/c2ccc(F)cc2F)nc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)nc1
Yield: 94 %

Procedure:
2-[(E)-2-(2,4-difluorophenyl)vinyl]-5-(phenylsulfonyl)pyridine (Example 26, 0.52 g, 1.45 mmol) and palladium hydroxide (20% wt. Pd on carbon, 100 mg, 0.14 mmol) were stirred in acetic acid (10 mL) and ethyl acetate (5 mL) under a balloon of hydrogen for 3 hours. The catalyst was removed by filtration and the filtrate washed with 4N sodium hydroxide solution (×2). The aqueous layers were extracted with dichloromethane. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give 2-[2-(2,4-difluorophenyl)ethyl]-5-(phenylsulfonyl)pyridine as a pale yellow solid (0.49 g, 94%). δH (500 MHz, d6 DMSO): 9.02 (1H, s), 8.23 (1H, dd, J=2.2, 8.2 Hz), 7.99 (2H, d, J=7.4 Hz), 7.70 (1H, t, J=7.4 Hz), 7.63 (2H, t, J=7.7 Hz), 7.48 (1H, d, J=8.2 Hz), 7.27 (1H, q, J=8.0 Hz), 7.11 (1H, td, J=2.0, 9.9 Hz), 6.94 (1H, td, J=1.9, 8.6 Hz), 3.07 (2H, t, J=7.7 Hz), 2.97 (2H, t, J=7.7 Hz); m/z (ES+) 360 [MH+].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]4)[S:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)#[CH:2].C(O)=[O:27]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]4)[S:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)(=[O:27])[CH3:2]
Reactant: C#Cc1ccc(-c2cc3sc(N4CCN(CC)CC4)cc3cn2)cc1
Reactant: O=CO
Product: CCN1CCN(c2cc3cnc(-c4ccc(C(C)=O)cc4)cc3s2)CC1

Procedure:
6-(4-Ethynylphenyl)-(4-ethylpiperazin-1-yl)thieno[3,2-c]pyridine (0.59 g) was reacted in formic acid (15 ml) at 100° C. for 12 hr. The reaction solution was evaporated, basified with an aqueous solution of potassium carbonate, and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried and concentrated. The resulting residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane system), to give 0.37 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[NH:9][C:7]=2[N:8]=1.[Br:14]N1C(=O)CCC1=O>CN(C)C=O>[Br:14][C:11]1[C:10](=[O:13])[NH:9][C:7]2[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=2[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ncc2ccc(=O)[nH]c2n1
Solvent: CN(C)C=O
Product: CSc1ncc2cc(Br)c(=O)[nH]c2n1
Reaction time: 18 h
Yield: 48.3 %

Procedure:
To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (1, 1.00 g, 5.18 mmol) in anhydrous dimethylformamide (25 mL) was added N-bromosuccinimide (0.99 g, 5.59 mmol) portionwise at room temperature, and the reaction mixture was stirred for 18 h. The mixture was concentrated, and the solid was triturated with hot water (1×20 mL), filtered, and washed with isopropanol to give title compound as a pale yellow solid (0.68 g, 2.50 mmol, 48%). ESMS m/z 272 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.88 (br. s., 1H), 8.84 (s, 1H), 8.47 (s, 1H), 2.57 (s, 3H).
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]([C:21](=[O:49])[NH:22][C@@H:23]([C:36](=[O:48])[NH:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][CH:42]=[CH:41]2)[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)[CH2:17][C:18](O)=[O:19])=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:50]([O:54][C:55]([NH:57][CH2:58][CH2:59][NH:60][CH2:61][CH2:62][NH:63][C:64](=[O:70])[O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:56])([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[C:50]([O:54][C:55]([NH:57][CH2:58][CH2:59][N:60]([CH2:61][CH2:62][NH:63][C:64]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:70])[C:18]([CH2:17][C@H:16]([NH:15][C:13](=[O:14])[O:12][C:8]([CH3:10])([CH3:9])[CH3:11])[C:21](=[O:49])[NH:22][C@@H:23]([C:36](=[O:48])[NH:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][CH:42]=[CH:41]2)[CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1)=[O:19])=[O:56])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2ncccc2c1
Reactant: CC(C)(C)OC(=O)NCCNCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)C(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2ncccc2c1
Yield: 72 %

Procedure:
To a solution of CDMT (37 mg, 0.20 mmol) in DCM (10 mL) and cooled to 0° C. was added N-methylmorpholine (0.023 mL, 0.20 mmol). The mixture was stirred for min before adding (3S)-3-{[(tert-butoxy)carbonyl]amino}-3-{[(1R)-1-[(quinolin-6-yl)carbamoyl]-3-[4-(trifluoromethyl)phenyl]propyl]carbamoyl}propanoic acid (110 mg, 0.18 mmol). The solution was stirred for 60 min at 0° C. The tert-butyl N-{2-[(2-{[(tert-butoxy)carbonyl]amino}ethyl)amino]ethyl}carbamate X was then added and the mixture stirred at r.t. overnight. The solution was washed with 1 M aq. K2CO3, 1 M aq. HCl, brine and dried over anhydrous MgSO4. The crude product was then purified on a silica gel column (100:1 CHCl3/MeOH) and finally crystallized from ethyl ether/hexane to give tert-butyl N-[(1S)-2-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-1-{[(1R)-1-[(quinolin-6-yl)carbamoyl]-3-[4-(trifluoromethyl)phenyl]propyl]carbamoyl}ethyl]carbamate XI (110 mg, 0.13 mmol, 72% yield). 1H NMR (CDCl3) 1.43 (s, 18H), 1.50 (s, 9H), 1.69 (brs, 2H), 2.03 (brs, 2H), 2.78 (brs, 2H), 3.23 (brs, 2H), 3.46 (brs, 4H), 4.60 (brs, 4H), 4.96-5.11 (m, 1H), 5.98-6.14 (m, 1H), 6.91-7.01 (m, 1H), 7.28-7.38 (m, 3H), 7.47-7.58 (m, 3H), 7.88-8.03 (m, 2H), 8.12 (d, J=7 Hz, 1H), 8.52 (s, 1H), 8.81 (brs, 1H), 9.31 (brs, 1H); 19F NMR (DMSO-d6) −61.75 (s, 3F); ESIMS found for C43H58F3N7O9 m/z 874 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8](Cl)=[O:9])=[N:3]1.[C:11]1([S:17]([N:20]2[C:28]3[CH:27]=[C:26]([Sn:29]([CH3:32])([CH3:31])[CH3:30])[CH:25]=[C:24]([NH2:33])[C:23]=3[CH:22]=[N:21]2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]([NH:33][C:24]2[CH:25]=[C:26]([Sn:29]([CH3:32])([CH3:31])[CH3:30])[CH:27]=[C:28]3[C:23]=2[CH:22]=[N:21][N:20]3[S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])=[O:9])=[N:3]1
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Reactant: Cc1cn(C)nc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cn(C)nc1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,4-Dimethyl-1H-pyrazole-3-carbonyl chloride (46 mg) in DCM (2.5 ml) was added over 5 min to 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (100 mg) in DCM (2.5 ml) and pyridine (0.023 ml). The reaction was stirred at room temperature for 2 h. Separately, 1,4-dimethyl-1H-pyrazole-3-carbonyl chloride (273 mg) in DCM (5 ml) was added over 10 min to 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (600 mg) in DCM (25 ml) and pyridine (0.2 ml). The reaction was stirred at room temperature for 1 h. The reactions were combined and separated between saturated sodium bicarbonate (aq) and DCM. The DCM was passed through a hydrophobic frit then dried. The residue was dissolved in DCM and purified using a silica cartridge, preconditioned with cyclohexane. The cartridge was eluted with cyclohexane:diethyl ether (1:1, v/v) then diethyl ether, then 10% methanol in diethyl ether and finally with 50% methanol in diethyl ether. Pure fractions were combined and dried to give title compound, 753 mg.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)[CH:8]=1)(=O)=O.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:18][O:17][C:11]1[CH:12]=[CH:13][C:14]2[C:9](=[CH:8][C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH:10]=1
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Reactant: OB(O)c1ccccc1
Product: COc1ccc2ccc(-c3ccccc3)cc2c1

Procedure:
The title compound was prepared by reacting 7-methoxy-2-naphthyl trifluoromethanesulfonate (3.01 g, 9.83 mmol) with phenylboronic acid (1.4 g, 12 mmol) according to method A to yield 1.95 g (85%) of a white solid mp 62-64° C.; 1H NMR (CDCl3) δ 3.95 (3H, s), 7.15 (1H, dd, J=2.56 Hz, J=8.79 Hz), 7.20 (1H, d, J=2.56 Hz), 7.36-7.39 (1H, m), 7.46-7.50 (2H, m), 7.60 (1H, dd, J=1.83 Hz, J=8.42 Hz), 7.70-7.73 (2H, m), 7.76 (1H, d, J=8.79 Hz), 7.84 (1H, d, J=8.42 Hz), 7.94 (1H, d, J=1.46 Hz); MS (EI) m/z 234 (M)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]1[O:20][CH3:21].[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]2[O:20][CH3:21])=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: COC(=O)c1cc(OC)cc(N2CC[C@H](N)[C@H](OC)C2)c1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(OC)cc(C(=O)OC)c3)C[C@H]2OC)nc1Cl
Yield: 87.7 %

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-3-(4-amino-3-methoxypiperidin-1-yl)-5-methoxybenzoate obtained in Example (257c) (about 0.25 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (48 mg, 0.22 mmol), WSC hydrochloride (139 mg, 0.73 mmol), HOBT (49 mg, 0.36 mmol), dichloromethane (2 mL) and DMA (2 mL), to obtain 87 mg of the title compound (88%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH2:8]Cl)(=[O:3])[CH3:2].[CH:11]([O-:13])=[O:12].[Na+].O>CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:11]([O:13][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:12]
Reactant: O=C[O-]
Reactant: CC(=O)OCC=C(C)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCC=C(C)COC=O
Temperature: 40 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
4-Acetoxy-2-methyl-1-chloro-2-butene (8.13 g, 50 mmol) was dissolved in dimethylformamide (25 ml) and placed in a 100 ml four neck flask. To this were added sodium formate powder (6.80 g, 100 mmol, 2 equivalents) and tetra n-butylammonium bromide (0.81 g, 2.5 mmol, 5 mol %). The mixture was stirred at 40° C. for 24 hours under heating. After completion of the reaction, the reaction mixture was poured into ice-cooled water (about 30 ml) and extracted with ether (50 ml) three times. The extracted ether layer was dried over anhydrous sodium sulfate. Evaporation of the ether followed by purification by silica gel column chromatography (ethyl acetate-hexane (=1:3)) gave 4-acetoxy-2-methyl-2-buten-1-ol formate (8.18 g, 47.5 mmol; Yield: 95.0%).
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][NH2:28])=[C:21]([CH3:29])[CH:20]=1.Cl>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][NH:28][C@H:4]2[CH2:5][CH2:6][C@H:1]([C:8]3[CH:17]=[CH:16][C:11]4[NH:12][C:13](=[O:15])[O:14][C:10]=4[CH:9]=3)[CH2:2][CH2:3]2)=[C:21]([CH3:29])[CH:20]=1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: Cc1cc(F)ccc1CCCN
Agent: Cl
Product: Cc1cc(F)ccc1CCCN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1

Procedure:
Coupling of ketone 5 and 3-(4-fluoro-2-methylphenyl)-1-propylamine, using the method given in Example 1, gave 6-(trans-4-[3-(4-fluoro-2-methylphenyl)propylamino]cyclohexyl}-3H-benzoxazol-2-one (630 mg, 56%) as the HCl salt: 1H NMR (500 MHz, DMSO-d6): δ 11.50 (s, 1H), 8.88 (s, 2H), 7.22-7.13 (m, 2H), 7.05-6.91 (m, 4H), 3.09-2.87 (m, 3H), 2.67-2.62 (m, 3H), 2.30 (s, 3H), 2.17-2.13 (m, 2H), 1.92-1.79 (m, 4H), 1.58-1.41 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][NH:5][CH:6]=1.Cl[C:14]1[N:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[Cl:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][N:5]([C:14]2[N:24]=[CH:23][CH:22]=[CH:21][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=1
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: Clc1c[nH]nc1-c1ccccc1
Product: CCOC(=O)c1cccnc1-n1cc(Cl)c(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 3.1 by reacting 4-chloro-3-phenyl-1H-pyrazole and ethyl 2-chloronicotinate. ESI-MS [M+H]+: 328.1
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].CN(C)CC[N:11]1[C:19]2[CH:18]=[CH:17][C:16](Cl)=[C:15]3[C:21](=[O:28])[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][C:27]=4[C:13]([C:14]=23)=[N:12]1>N1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:16]1[CH:17]=[CH:18][C:19]2[NH:11][N:12]=[C:13]3[C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[C:21](=[O:28])[C:15]=1[C:14]=23
Reactant: CN(C)CCn1nc2c3c(c(Cl)ccc31)C(=O)c1cnccc1-2
Reactant: CN(C)CCN
Solvent: c1ccncc1
Product: CN(C)CCNc1ccc2[nH]nc3c2c1C(=O)c1cnccc1-3
Temperature: 80 °C

Procedure:
Under a nitrogen atmosphere N,N-dimethylethylenediamine (1.79 mL) is added to a stirred solution of 2-[2-(dimethylamino)ethyl]-5-chloroisoquino[5,6,7-cd]indazole-6(2H)-one (0.539 g) in pyridine (6.80 mL) and the resulting solution is heated at 80° C. for 12 hours. The pyridine and excess N,N-dimethylethylenediamine are removed by roto-evaporation and the obtained residue is purified by silica gel column chromatography eluting first with methylene chloride, then with methylene chloride/methanol 95/5 and finally with methylene chloride/methanol/concd. ammonia from 95/5/0.5 to 95/5/1 v/v/v. The fractions containing the yellow desired product are pooled and the solvents roto-evaporated. The obtained residue (0.529 g) is crystallized from diisopropylether to give 2-[2-(dimethylamino)ethyl)]-5-[[2-(dimethylamino)ethyl]amino]isoquino[5,6,7-cd]indazole-6(2H)-one as a yellow powder (0.291 g).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[C:17]([CH3:18])=[N:16][CH:15]=[N:14]1.[CH2:19]([OH:22])[CH:20]=[CH2:21]>CN(C=O)C>[CH2:19]([O:22][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[C:17]([CH3:18])=[N:16][CH:15]=[N:14]1)[CH:20]=[CH2:21]
Reactant: Cc1ncnn1-c1ccc([N+](=O)[O-])cc1F
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1-n1ncnc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
A suspension of NaH (0.675 g, 16.88 mmol, 60% dispersion in mineral oil) in DMF (25 mL) was cooled to 0° C. A solution 1-(2-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole (2.50 g, 11.25 mmol) was added dropwise. Allyl alcohol (0.784 g, 13.5 mmol) was added via syringe over 5 min. The reaction mixture was allowed to warm up to room temperature. After 30 min, TLC showed completion of reaction. It was slowly quenched with water (10 mL), diluted with brine (100 mL), and extracted with EtOAc (3×50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (20-80% EtOAc/hexane, linear gradient). Pure fractions were concentrated under reduced pressure to afford 1-(2-(allyloxy)-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole (1.5 g 51% yield) as a yellow-brown colored solid. LC-MS (M+H)+=261.0. 1H NMR (400 MHz, CDCl3) δ ppm 8.02-7.94 (m, 3H), 7.58 (d, 1H, J=8.4 Hz), 5.98-5.89 (m, 1H), 5.37-5.32 (m, 2 H), 4.69-4.70 (m, 2H), 2.403 (s, 3H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[CH:34]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH2:35].C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].CN(C=O)C>[CH2:37]([O:36][C:34]([C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=2)[C:7]=1[CH3:8])=[CH2:35])[CH2:38][CH2:39][CH3:40]
Reactant: C=COCCCC
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(OCCCC)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Temperature: 100 °C
Yield: 28.5 %

Procedure:
5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 1 (d), 101.5 mg, 0.17 mmol), bis[1,2-bis(diphenylphosphino)ethane]-palladium (0) (16.5 mg, 18.3 μmol), n-butyl vinyl ether (60 μl, 0.46 mmol), triethylamine (0.5 ml, 3.6 mmol) and DMF (6 ml) were placed in a Schlenk vessel equipped with a magnetic stirring bar. The vessel was purged with argon, sealed, and heated at 100° C. overnight. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (27.3 mg, 28%).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:6]=[C:5]([Cl:33])[N:4]=1.[CH3:34][O-:35].[Na+]>C1COCC1.O>[Cl:33][C:5]1[N:4]=[C:3]([CH2:2][O:35][CH3:34])[C:8]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:6]=1
Reactant: C[O-]
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CBr)c12
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1nc(Cl)cc2c1c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(Bromomethyl)-6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (from the synthesis of Intermediate 11B/Step 2; 64 mg, 0.123 mmol) was dissolved in THF (1.5 mL), charged with sodium methoxide (0.080 mL, 0.370 mmol, 4.6 M), and allowed to stir at room temperature for 30 min. The reaction mixture was diluted with water, extracted with ethyl acetate, and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (5-50% EtOAc/hexanes) to give 6-chloro-3-methoxy-4-(methoxymethyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine. MS ESI calc'd. For C28H24ClN3O2 [M+1]+ 470. found 470.