Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7](I)=[N:6]2)[CH2:4][CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[CH:1]1([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[N:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)nn2C1CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nn2C1CCC1
Temperature: 80 °C

Procedure:
Nitrogen was bubbled into a mixture of 1-cyclobutyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (60.0 mg, 0.190 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (64.4 mg, 0.194 mmol), Na2CO3 (50.5 mg, 0.476 mmol), and Pd(PPh3)4 (13.7 mg, 0.0119 mmol) in DMF (4 mL)/water (1 mL) for 5 min, then the mixture was heated under nitrogen to 80° C. (bath temp.) for 17 h. The solvents were evaporated, water was added, the mixture was extracted with CH2Cl2 (3×20 mL), and the combined extracts were washed with brine and dried over MgSO4. MgSO4 was filtered off, and the filtrate was concentrated and chromatographed on an SCX column (1 g/6 mL barrel). The amine-containing fraction was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-11)→1% MeOH in CH2Cl2 (12-28)→2% MeOH in CH2Cl2 (29-46)], yielding the title compound as off-white solid. 1H NMR (CDCl3, 400 MHz): δ=1.87-2.04 (m, 2H), 2.48-2.58 (mc, 2H), 2.86-2.98 (mc, 2H), 5.50 (quint, J=8.0 Hz, 1H), 5.57 (brs, 2H), 7.47-7.52 (m, 1H), 7.53-7.58 (m, 2H), 7.96 (dd, J=1.6, 8.3 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 8.19-8.23 (m, 2H), 8.31 (d, J=8.6 Hz, 1H), 8.42 (s, 1H), 8.49-8.52 (m, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=14.99 (−), 29.91 (2C, −), 50.61 (+), 98.68 (Cquart), 119.59 (+), 126.53 (+), 126.97 (Cquart), 127.56 (2C, +), 128.66 (+), 128.79 (2C, +), 129.00 (+), 129.53 (+), 134.83 (Cquart), 136.53 (+), 139.14 (Cquart), 143.40 (Cquart), 148.22 (Cquart), 154.00 (Cquart), 155.53 (+), 157.92 (Cquart), 158.18 (Cquart). MS (ES+): m/z 393.1 (53) [MH+]. HPLC: tR=3.1 min (OpenLynx, nonpolar—5 min), 3.6 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[S:10].[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13]>C(N(CC)CC)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10][CH2:13][CH2:12][C:11]([OH:15])=[O:14]
Reactant: C=CC(=O)O
Reactant: S=C1Cc2ccccc2N1
Solvent: CCN(CC)CC
Product: O=C(O)CCSc1cc2ccccc2[nH]1

Procedure:
One liter of triethylamine is added slowly in the course of 2 hours 30 minutes to a vigorously stirred suspension of 194 g (1.3 mol) of 2-indolinethione (prepared according to Y. Nakisumi and Coll. Chem. Pharm. Bull. 1984, 32, (3), 877) in 108 g (1.5 mol) of acrylic acid. The mixture is brought to reflux for 12 hours while stirring is maintained, and then cooled and concentrated under vacuum. The residue is taken up with 10% strength aqueous sodium bicarbonate solution and the mixture is filtered. The filtrate is acidified with aqueous hydrochloric acid solution. The precipitate formed is drained, washed with water and dried. It is recrystallized in toluene.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30]C5C(C)=NC=CC=5)=[CH:26][CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[C:39]1[CH:40]=[CH:41][C:42]([CH3:45])=[N:43][CH:44]=1>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([O:30][C:39]5[CH:44]=[N:43][C:42]([CH3:45])=[CH:41][CH:40]=5)=[CH:28][CH:29]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:16])([F:17])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)cn1
Reactant: Cc1ncccc1Oc1ccc(-c2cn(C3CCc4c(F)cccc4N(CC(F)(F)F)C3=O)nn2)cc1
Product: Cc1ccc(Oc2ccc(-c3cn(C4CCc5c(F)cccc5N(CC(F)(F)F)C4=O)nn3)cc2)cn1

Procedure:
Prepared as for 6-fluoro-3-(4-{4-[(2-methylpyridin-3-yl)oxy]phenyl}-1H-1,2,3-triazol-1-yl)-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one, using 5-hydroxy-2-methylpyridine.
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][N:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:28])=O>>[CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([C:23]([Cl:28])=[O:25])=[CH:19][N:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccc(-c2ncc(C(=O)O)cn2)cc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCc1ccc(-c2ncc(C(=O)Cl)cn2)cc1

Procedure:
2-(4-n-Decylphenyl)pyrimidine-5-ylcarboxylic acid (1.5 g) was heated together with excess thionyl chloride for 4 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 2-(4-n-decylphenyl)pyrimidine-5-ylcarboxylic acid chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])(=[O:12])=[O:11])([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])(=[O:12])=[O:11]
Reactant: [H][H]
Reactant: CCN(CC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCN(CC)S(=O)(=O)c1ccccc1N
Yield: 104.6 %

Procedure:
In a pressure vessel a mixture of 133 g of o-nitro-N,N-diethylbenzenesulfonamide, 5 g of 10% palladium on carbon, and 500 ml of ethyl acetate was shaken at 130° under 500 psi hydrogen pressure until hydrogen was no longer absorbed. The reaction mixture was cooled and the catalyst filtered off. Evaporation of the solvent in-vacuo gave 123 g of o-amino-N,N-diethylbenzenesulfonamide as a viscous oil which slowly crystallized to a solid, m.p. 45°-51°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:12](Cl)Cl>>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: ClCCl
Reactant: O=C(O)Cc1cccc(Br)c1
Product: COC(=O)Cc1cccc(Br)c1

Procedure:
To a solution of 3-bromophenylacetic acid (10 g, 46 mmol) in CH2Cl2 (20 mL) was added CH2N2 (Et2O) until yellow coloration persisted. The resulting reaction mixture was quenched with AcOH, and diluted with a NaHCO3 solution and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated to provided the (3-Bromo-phenyl)-acetic acid methyl ester compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13]O)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.F[P-](F)(F)(F)(F)F.[C:39]([C:43]1[CH:44]=[C:45]([NH2:50])[C:46]([NH2:49])=[CH:47][CH:48]=1)([CH3:42])([CH3:41])[CH3:40]>CN(C)C=O.O>[C:39]([C:43]1[CH:48]=[CH:47][C:46]2[NH:49][C:13]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][OH:12])=[N:50][C:45]=2[CH:44]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CO)c1nc2cc(C(C)(C)C)ccc2[nH]1
Reaction time: 0.17 h
Yield: 21.9 %

Procedure:
(S)-2-((tert-Butoxycarbonyl)amino)-3-hydroxypropanoic acid (226 mg, 1.10 mmol) was dissolved in N,N-dimethylformamide (5 mL) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid-hexafluorophosphate (440 mg, 1.10 mmol) was added. The reaction was stirred for 10 minutes then 4-(tert-butyl)benzene-1,2-diamine (164 mg, 1.00 mmol) was added and the reaction mixture stirred for 18 hours. The reaction mixture was diluted with water and extracted twice with ethyl ether. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo. The residue was dissolved in 1,2-dichloroethane and anhydrous magnesium sulfate was added. The reaction was stirred at 65° C. for 18 hours to complete the dehydration. The reaction mixture was filtered and loaded directly onto a 4 g silica gel column for purification. The column was eluted with 0-10% methanol in dichloromethane to afford 73 mg of product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][OH:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH:13]=[O:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(CO)COC1(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(C=O)COC1(C)C
Reaction time: 8 h

Procedure:
To a solution of (36) (80 mg, 0.346 mmol) stirring in CH2Cl2 (2 mL), under a nitrogen atmosphere, was added pyridinium chlorochromate (150 mg, 0.694 mmol). The reaction mixture was allowed to stir overnight then filtered through a plug of silica gel. The crude aldehyde was carried on to the following step.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:18]=1[O:19][CH3:20])[C:13]([OH:15])=O)([CH3:9])[CH3:8].[CH2:24]([C:31]1[S:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Sn](Cl)(Cl)(Cl)Cl>ClCCl.O.CN(C=O)C>[CH2:24]([C:31]1[S:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[C:32]=1[C:13]([C:12]1[CH:16]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:18]([O:19][CH3:20])=[C:10]([CH:7]([CH3:8])[CH3:9])[CH:11]=1)=[O:15])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(Cc2cc3ccccc3s2)cc1
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3)sc3ccccc23)cc1C(C)C
Temperature: -78 °C

Procedure:
A drop of DMF was added to a solution of oxalyl chloride (1.4 mL, 16.2 mmmol), 3,5-diisopropyl-4-methoxybenzoic acid (4.0 g, 14.7 mmol) in dichloromethane under a dry nitrogen atmosphere. After 4 h the solvent was removed and the resulting solid was triturated with petroleum ether and dried in vacuo. To this solid was added 2-benzyl-benzo[b]thiophene (3.32 g, 13.4 mmol) and dichloromethane (75 mL). The resulting solution was stirred under a dry nitrogen atmospher and cooled to -78° C. Tin tetrachloride (3.44 mL, 29.48 mmol) was added dropwise over a 20 minute period. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was added to water and extracted with ether. The ether extract was washed with water and brine. Silica gel was added and the solvent was removed. The adsorbate was flash chromatographed (gradient, petroleum ether to 95:5 petroleum ether:ethyl acetate). The solvent was removed and the solid was triturated with ether to give the title compound as a a white solid (3.68 g, 62%): mp 124-125° C.; NMR (CDCl3); δ 7.75 (ddd, J=8, 2, 1 Hz, 1H), 7.64 (s, 2H), 7.48 (ddd, J=8, 2, 1, 1H), 7.30-7.19 (m, 7H), 4.22 (s, 2H), 3.80 (s, 3H) 3.35 (septuplet, J=7 Hz, 2H), 1.19 (d, J=7 Hz, 12H); MS (+FAB): 443 (100%, M+H); Anal. Calc. for C29H30O2S: C, 78.69, H, 6.83, N, 0.00. Found: C, 78.57, H, 6.88, N, 0.14.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([I:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH:21][CH3:22]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:21]([CH3:22])[CH3:20])[C:11]([I:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1I

Procedure:
The title compound was prepared from (5-chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B1) (399 mg, 1 mmol) and dimethylamine (5.6 N in EtOH, 0.36 mL, 2 mmol) in THF (3 mL) at 65° C. for 18 h in a sealed tube according to the general procedure C. Obtained as a yellow solid (386 mg).
Reaction SMILES: C([O:5][C:6]([CH:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[N:9]1[C:13]2[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=2[N:11](C(OC(C)(C)C)=O)[C:10]1=[O:26])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[I:18][C:15]1[CH:16]=[CH:17][C:12]2[NH:11][C:10](=[O:26])[N:9]([CH:8]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:6]([OH:7])=[O:5])[C:13]=2[CH:14]=1
Reactant: CC(C)(C)OC(=O)C(c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(I)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(c1ccccc1)n1c(=O)[nH]c2ccc(I)cc21
Temperature: 25 °C

Procedure:
1.50 g (2.73 mmol) of tert-butyl 3-(tert-butoxycarbonylphenylmethyl)-5-iodo-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (XIIb) were dissolved in dichloromethane (16 ml) and, while stirring at room temperature, trifluoroacetic acid (10 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 1.10 g (100%) of yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:18][S:17][C:14]1[CH:13]=[CH:12][C:11]([NH:10][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][N:15]=1
Reactant: CSc1ccc(N)cn1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CSc1ccc(NCc2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.3 %

Procedure:
To 344 μL (3.20 mmol) of 4-fluorobenzaldehyde and 449 mg (3.20 mmol) of 5-amino-2-methylthio-pyridine dissolved in 8 mL dichloromethane was added 1.11 g (5.25 mmol) sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for 5 h, and partitioned between ethyl acetate and water, dried over MgSO4 and concentrated to obtain 320 mg of 5-[(4-fluorobenzyl)amino]-pyridin-2-yl methyl sulfide, pure by 1H NMR.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])([C:14](OCC)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:14][OH:15])([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(Cc2ccccc2F)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC1(Cc2ccccc2F)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A stirred solution of ethyl 1-benzyl-4-(2-fluorobenzyl)piperidine-4-carboxylate (1.85 g, 5.2 mmol) in diethyl ether was cooled on ice/sodium chloride. Lithium aluminium hydride (5.8 mL, 1.0 M in diethyl ether) was added drop wise. After stirring at room temperature for 2 hrs the mixture was re-cooled on ice, quenched with water/sodium hydroxide (10%) and stirred at room temperature for 1 hrs. The solids were filtered off, and the organic layer was dried over disodium sulphate, filtrated and concentrated. The crude material was purified on silica (dichloromethane/ethanol) to give 1.0 g (61%) the subtitle compound.
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[CH:55]=[C:54]([O:56][CH2:57][C@@H:58]2[CH2:62][O:61][C:60]([CH3:64])([CH3:63])[O:59]2)[N:53]=[C:52]([S:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[C:69]([F:73])[C:68]=2[F:74])[N:51]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:74][C:68]1[C:69]([F:73])=[CH:70][CH:71]=[CH:72][C:67]=1[CH2:66][S:65][C:52]1[N:51]=[C:50]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:55]=[C:54]([O:56][CH2:57][C@@H:58]2[CH2:62][O:61][C:60]([CH3:64])([CH3:63])[O:59]2)[N:53]=1
Reactant: CC1(C)OC[C@@H](COc2cc(Cl)nc(SCc3cccc(F)c3F)n2)O1
Reactant: NS(=O)(=O)N1CCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1(C)OC[C@@H](COc2cc(NS(=O)(=O)N3CCC3)nc(SCc3cccc(F)c3F)n2)O1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step iv) using a mixture of azetidine-1-sulfonamide (prepared according to patent WO 2004/011443, 0.24 g), tris(dibenzylideneacetone)dipalladium (0) (0.11 g), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (55 mg), cesium carbonate (0.57 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]-pyrimidine (0.47 g) in dioxane (8 mL). Purification was by column chromatography on silica using EtOAc/isohexane (3:7) as eluent to give the subtitle compound as a pale yellow solid. Yield: 0.49 g
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14](Br)[C:15]#[CH:16].C(=O)([O-])[O-].[K+].[K+].[Br-]>C(#N)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:16][C:15]#[CH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 44.7 %

Procedure:
To a solution of 10.0 g (54.8 mmol) of tert-butyl-1-piperazine carboxylate in 60 mL acetonitile was added 5.20 mL (60.4 mmol) propargyl bromide and 37.9 g (274 mmol) anhydrous potassium carbonate. Additional propargy bromide, 1.5 mL, was added after stirring for 36 hours at room temperature. The residue was evaporated to dryness. Dichloromethane, 50 mL, and water, 50 mL, were added. The reaction mixture was extracted with CH2Cl2, 4×40 mL, dried over magnesium sulfate, and evaporate to provide a brown oil. The oil was dissolved in dichloromethane and purify with a RT Scientific system using hexane/ethyl acetate gradient to yield 5.5 g (46%) of yellow oil, which ultimately crystallized upon standing.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH2:28][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)[CH:30]=[CH:31][CH:32]=1)(=[O:23])=[O:24]
Reactant: CS(=O)(=O)c1cccc(C=O)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: CS(=O)(=O)c1cccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-methylsulfonylbenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-methylsulfonylphenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[N:14]=[CH:13][CH:12]=[CH:11][C:7]=3[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=[N:2]1.C(N(CC)CC)C.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:41])=[C:27]([CH:40]=1)[C:28]([NH:30][C:31]1[N:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=1)=[O:29].[OH-].[Na+]>ClCCl.CO>[NH:2]1[C:3]2[C:11]3[CH:12]=[CH:13][N:14]=[CH:6][C:7]=3[N:8]([C:37]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:40]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=4[CH3:41])=[N:36][CH:35]=3)=[O:38])[CH2:9][CH2:10][C:4]=2[CH:5]=[N:1]1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1cnc2c(c1)NCCc1cn[nH]c1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3ccncc32)cn1

Procedure:
To a solution of 2 mmol 1,4,5,6-tetrahydropyrazolo[3,4-d]pyrido[3,2-b]azepine and 10 mmol of triethylamine in 25 ml of dichloromethane is added 4.2 mmol of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride. After stirring over the mixture is worked-up as described for Example 1 and the initial solid treated with 1N NaOH in methanol as described for Example 1 to give the product as a solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:18]=[C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])[CH:16]=2)[CH:10]=1)(=O)=O.[CH:35]([NH2:38])([CH3:37])[CH3:36].[CH:39]([OH:41])=[O:40].ClC1C=C(N2C(C3C=CC=C(OCCCN(C)C)C=3)=CC(C(N3CC(=O)NC3)=O)=N2)C=CC=1>O1CCCC1>[CH:39]([OH:41])=[O:40].[Cl:26][C:22]1[CH:21]=[C:20]([N:19]2[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:6][NH:38][CH:35]([CH3:37])[CH3:36])[CH:10]=3)=[CH:16][C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])=[N:18]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)N
Reactant: CS(=O)(=O)OCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Agent: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: O=CO
Solvent: C1CCOC1
Product: CC(C)NCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 121A and isopropylamine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 29 mg (28% of theory) of the title compound are obtained.
Reaction SMILES: C[N:2](C)[C:3](=[N:5][C:6](=[S:18])[C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:9])[CH3:8])[CH3:4].NOS(O)(=O)=O.N1C=CC=CC=1.CO>C(O)C>[CH3:4][C:3]1[N:5]=[C:6]([C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:9])[CH3:8])[S:18][N:2]=1
Reactant: CC(=NC(=S)C(C)(C)NC(=O)OC(C)(C)C)N(C)C
Agent: NOS(=O)(=O)O
Solvent: CO
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1nsc(C(C)(C)NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A mixture of tert-butyl 1-(1-(dimethylamino)ethylideneamino)-2-methyl-1-thioxopropan-2-ylcarbamate (2.9 g, 10 mmol), hydroxylamine-O-sulfonic acid (CAN 2950-43-8, 1.37 g, 12 mmol), pyridine (1.6 g, 20.2 mmol) and methanol (4 mL) in ethanol (20 mL) was stirred at room temperature for 2 h. After evaporation of solvents, the residue was diluted with ethyl acetate (40 mL) and water (40 mL). The organic layer was washed with brine (40 mL), dried over anhydrous sodium sulfate and concentrated to give crude product (2.5 g, 96%) as yellow oil. The product was used directly in the next step without further purification; MS (EI): m/e 258.2 [M+H]+.