Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]2[N:12]([CH:15]([C:17]3[C:18]([F:28])=[C:19]4[C:24](=[CH:25][C:26]=3[F:27])[N:23]=[CH:22][CH:21]=[CH:20]4)[CH3:16])[N:13]=[N:14][C:9]2=[N:8][CH:7]=1)=[CH2:5])C.Cl>CO>[F:28][C:18]1[C:17]([CH:15]([N:12]2[C:10]3=[N:11][C:6]([C:4](=[O:3])[CH3:5])=[CH:7][N:8]=[C:9]3[N:14]=[N:13]2)[CH3:16])=[C:26]([F:27])[CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2
Reactant: C=C(OCC)c1cnc2nnn(C(C)c3c(F)cc4ncccc4c3F)c2n1
Agent: Cl
Solvent: CO
Product: CC(=O)c1cnc2nnn(C(C)c3c(F)cc4ncccc4c3F)c2n1
Yield: 94.1 %

Procedure:
A solution of 6-(1-(6-(1-ethoxyvinyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)ethyl)-5,7-difluoroquinoline (100.0 mg, 0.24 mmol) and 3 N HCl (0.1 mL) in CH3OH (10 mL) was stirred at 50° C. for 2 hours. The solvent was removed under reduced pressure. The reaction mixture was concentrated in vacuo to give the title compound as yellow solid (80.0 mg, 96%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.23 (s, 1H), 9.01 (dd, 1H), 8.53 (d, 2H), 7.76 (d, 1H), 7.64 (dd, 1H), 6.87 (q, 1H), 2.49 (s, 3H), 2.40 (d, 3H). LCMS (method A): [MH]+=355, tR=5.36 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]3[N:15]([CH3:19])[C:16](=[O:18])[NH:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:14]3[N:15]([CH3:19])[C:16](=[O:18])[N:17]([CH2:26][C:25]4[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Cn1c(=O)[nH]c2cccc(Nc3ccc(Cl)cc3)c21
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)n(C)c3c(Nc4ccc(Cl)cc4)cccc32)cc1
Temperature: 70 °C
Reaction time: 1.67 h

Procedure:
A mixture of 7-[(4-chlorophenyl)amino]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.27 g, 1.0 mmol), 4-methoxybenzyl chloride (0.17 ml, 1.20 mmol), potassium carbonate (0.21 g, 1.50 mmol) and N,N-dimethylformamide (1 ml) was stirred at 70° C. for 100 min. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (30 ml). The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was flash chromatographed eluting with a 15% ethyl acetate/hexanes to give 0.39 g (quant.) of the title compound as a powder.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:13]2[NH:14][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][C:12]=2[C:11]([CH3:23])([CH3:22])[CH2:10][NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=[O:29]>>[CH:1]([O:4][C:5]([C:7]1[C:13]2[NH:14][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][C:12]=2[C:11]([CH3:23])([CH3:22])[CH2:10][N:9]([C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:33]([F:34])=[C:25]([F:24])[CH:26]=2)[CH:8]=1)=[O:6])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2c([nH]1)C(C(=O)OC(C)C)=CNCC2(C)C
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Product: CCOC(=O)c1cc2c([nH]1)C(C(=O)OC(C)C)=CN(C(=O)c1ccc(F)c(F)c1)CC2(C)C

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 by using 4,4-dimethyl-1,4,5,6-tetrahydro-pyrrolo[2,3-d]azepine-2,8-dicarboxylic acid 2-ethyl ester 8-isopropyl ester and 3,4-difluoro-benzoyl chloride. 1H-NMR(CDCl3): δ 11.11 (1H, s), 7.83 (1H, s), 7.48 (1H, m), 7.27 (1H, m), 6.87 (1H, d), 5.10 (1H, m), 4.33 (2H, q), 3.92 (2H, s), 1.37 (3H, t), 1.33 (6H, s), 1.21 (6H, d). MS (ES): 461 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Cl)=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2].[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][CH:19]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[CH:19]2)=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Cl)nc1-c1ccccc1
Reactant: c1ccc2[nH]cnc2c1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-n2cnc3ccccc32)nc1-c1ccccc1
Temperature: 120 °C
Yield: 61.8 %

Procedure:
A mixture of 2-chloro-4-phenylthiazole-5-carboxylic acid ethyl ester (134 mg, 0.5 mmol), benzimidazole (Aldrich) (73.8 mg, 0.625 mmol) and LiN(TMS)2 (1N tetrahydrofuran solution, 0.63 ml) in tetrahydrofuran (2 ml) was heated in a micro-wave oven at 120° C. for 30 min. Water (3 ml) was added and the mixture was filtered, washed with water and ethyl acetate, dried in air flow to give 2-(benzoimidazol-1-yl)-4-phenylthiazole-5-carboxylic acid ethyl ester (108 mg, 61%). The aqueous solution was concentrated to remove tetrahydrofuran and then extracted with ethyl acetate to recover an additional amount of the product (100 mg, 75% pure). 1H-NMR (CDCl3) 8.84 (s, 1H); 8.16 (d, 1H); 7.81-7.90 (m, 3H); 7.39-7.58 (m, 5H); 4.37 (q, 2H); 1.27 (t, 3H). MS M/z 350 (M+1).
Reaction SMILES: Cl.Cl.[C@H:3]12[CH2:9][C@H:6]([NH:7][CH2:8]1)[CH2:5][N:4]2[CH2:10][C:11]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][C:21]3[S:22][C:23]4[C:24]([N:29]=3)=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][C:14]=2[O:13][CH:12]=1.[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:7]2[CH2:8][C@@H:3]3[CH2:9][C@H:6]2[CH2:5][N:4]3[CH2:10][C:11]2[C:15]3[CH:16]=[CH:17][C:18]([O:20][C:21]4[S:22][C:23]5[C:24]([N:29]=4)=[N:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][C:14]=3[O:13][CH:12]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1cnc2nc(Oc3ccc4c(CN5C[C@@H]6C[C@H]5CN6)coc4c3)sc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3Cc2coc3cc(Oc4nc5ncccc5s4)ccc23)cc1
Temperature: 25 °C
Yield: 17.3 %

Procedure:
A mixture of (1S,4S)-2-[3-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-benzofuran-6-yloxy]-thiazolo[4,5-b]pyridine dihydrochloride (50 mg, 0.11 mmol), 4-bromomethyl-benzoic acid methyl ester (28 mg, 0.12 mmol), and K2CO3 (38 mg, 0.28 mmol) in CH3CN (0.4 mL) was stirred at rt. Upon reaction completion, the mixture was concentrated, re-dissolved in DMF and purified by reverse phase HPLC to provide the title compound (10 mg, 16%). MS (ESI): mass calculated for C29H26N4O4S, 526.17; m/z found, 527.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.57 (dd, J=4.8, 1.6, 1H), 8.05-7.96 (m, 3H), 7.77 (d, J=8.5, 1H), 7.58 (dd, J=7.8, 4.3, 2H), 7.45 (d, J=8.3, 2H), 7.32-7.28 (m, 1H), 7.21 (dd, J=7.9, 4.8, 1H), 3.91 (s, 3H), 3.90-3.69 (m, 2H), 3.41-3.27 (m, 2H), 2.96-2.90 (m, 1H), 2.85-2.81 (m, 1H), 2.74-2.66 (m, 2H), 1.77 (s, 2H), 1.47 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>>[CH3:19][C:17]1[CH:18]=[C:13]([CH:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:26](=[O:29])[CH2:27][CH3:28])[N:7]=2)=[O:9])[CH3:12])[CH:14]=[N:15][C:16]=1[O:20][CH2:21][C:22]([F:24])([F:25])[F:23]
Reactant: Cc1cc(C(C)NC(=O)c2ccnc(N)n2)cnc1OCC(F)(F)F
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1nccc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (20 mg, 0.06 mmol, Step-1, single enantiomer) and propionyl chloride (26 mg, 0.28 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:31]([OH:33])=[O:32])[CH2:24][C:25]1C=CC=CC=1)=[O:21])[CH2:13][C:14]1[CH:19]=CC=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([C:37]1C=CC(OC(=O)[C@H](CC2C=CC=CC=2)NC(OCC2C=CC=CC=2)=O)=CC=1)([O-])=O.N[C@H](C(O)=O)CC1C=CC=CC=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:19][CH2:14][CH2:13][C@H:12]1[C:20]([NH:22][C@H:23]([C:31]([OH:33])=[O:32])[CH:24]([CH3:25])[CH3:37])=[O:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O

Procedure:
N-benzyloxycarbonyl-L-phenylalanyl-L-phenyl-alanine (m.p. 148°-151° C.) from N-benzyloxycarbonyl-L-phenylalanine 4-nitrophenyl ester and L-phenylalanine.
Reaction SMILES: C(OC([NH:11][C:12]1[C:13]([F:32])=[CH:14][C:15]([F:31])=[C:16]([C:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH:23]=2)[CH:17]=1)=O)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:11][C:12]1[C:13]([F:32])=[CH:14][C:15]([F:31])=[C:16]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:19]2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(NC(=O)OCc3ccccc3)c(F)cc2F)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N)c(F)cc2F)CC1
Reaction time: 72 h
Yield: 123.6 %

Procedure:
A mixture of tert-butyl 4-(5-{[(benzyloxy)carbonyl]amino}-2,4-difluorophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (1.60 g, 3.60 mmol) and 5% Pd/C (320 mg, 0.100 mmol) in ethyl acetate (25.0 mL) and methanol (25.0 mL) was hydrogenated at room temperature for 72 hours using hydrogen bomb (200 psi). The reaction mixture was filtered through Celite and washed with EtOAc/MeOH (1:1, 3×50 mL). The filtrate was concentrated in vacuo to afford tert-butyl 4-(5-amino-2,4-difluorophenyl)-1-piperidinecarboxylate (1.39 g, 100%). 1H NMR (400 MHz, CDCl3) δ 6.73 (t, 1H, J=10.6 Hz), 6.60-6.54 (dd, 1H, J=7.6, 6.57 Hz), 4.20 (br, 2H), 3.55 (s, 2H), 2.96-2.72 (m, 3H), 1.79-1.71 (m, 2H), 1.58-1.52 (m, 2H), 1.47 (s, 9H); ESMS m/e: 257.3 (M−56).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[C:27]([Br:37])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[Br:37][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]3[C:6]4[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9]3)[S:21][CH:22]=2)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]([F:35])([F:34])[F:36]
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: O=C(CBr)Nc1nc(-c2ccc(OCC(F)(F)F)c(Br)c2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3ccc(OCC(F)(F)F)c(Br)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.279 mmol) with 2-bromo-N-{4-[3-bromo-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}acetamide (158 mg, 0.333 mmol) in the presence of NaH (10 mg, 0.416 mmol) in dry DMF (5.0 mL) to give 30 mg of the product as a white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 3.17 (s, 3H), 3.39 (s, 3H), 4.91 (d, J=8.7 Hz, 2H), 5.32 (s, 2H), 6.22 (s, 1H), 7.30-7.38 (m, 2H), 7.69 (s, 1H), 7.89-7.95 (m, 1H), 8.17 (m, 1H), 12.65 (br s, 1H); APCI-MS (m/z) 572.27 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:9][C:10](OC(C)(C)C)=[O:11].CC(C[AlH]CC(C)C)C.[Cl-].[NH4+].Cl>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:9][CH:10]=[O:11]
Reactant: CCCCCCCCCCC[C@H](CC(=O)OC(C)(C)C)OC1CCCCO1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC[C@H](CC=O)OC1CCCCO1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
(1J.a) 9.2 g of t-butyl (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]tetradecanoate are dissolved in 115 ml of toluene while gassing with argon and with the exclusion of moisture and cooled to -75° C. 26.5 ml of a 1.2M DIBAH solution in toluene are then added dropwise within 1/2 hour in such as manner that the temperature does not exceed -70° C. The mixture is stirred at -75° C. for a further one hour. There are then added dropwise 7.4 ml of saturated ammonium chloride solution and subsequently 15.5 ml of 1N hydrochloric acid at -70° C. The cooling bath is removed and the mixture is left to warm to room temperature. After stirring at room temperature for one hour the organic phase is separated and washed with water. The organic phase is dried, filtered and evaporated. The material obtained is chromatographed on silica gel. There is obtained [(R)-3-[(tetrahydro-2H-pyran-2-yl)oxyl]tetradecanal as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Br[C:14]1[CH:15]=C(C=C(OC(C)C)[CH:23]=1)C(OC)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:14]([CH3:15])[CH3:23])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: COC(=O)c1cc(Br)cc(OC(C)C)c1
Product: COC(=O)c1ccc(OC(C)C)c(Cl)c1

Procedure:
Prepared from methyl 3-chloro-4-hydroxybenzoate according to the procedure for methyl 3-bromo-5-isopropoxybenzoate. LCMS-ESI (m/z) calculated for C11H13ClO3: 228.7. found 229.1 [M+H]+, tR=3.90 min. 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=2.1 Hz, 1H), 7.89 (dd, J=8.7, 2.2 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 4.67 (dt, J=12.2, 6.1 Hz, 1H), 3.89 (s, 3H), 1.37 (dd, J=34.4, 30.1 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3](=[O:19])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][N:5]2[CH2:4][C:3]([N:2]([CH3:1])[CH3:20])=[O:19])=[CH:9][C:10]=1[O:17][CH3:18]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(CC(=O)N(C)C)CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc2c(cc1N)N(CC(=O)N(C)C)CC2

Procedure:
A solution of N,N-dimethyl-2-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]acetamide (0.16 g, 1.72 mmol) in absolute ethanol (50 mL) and ethyl acetate (5 mL) was hydrogenated overnight at 45 psi with catalytic 10% Pd/C. The catalyst was removed by vacuum filtration through a celite pad which was rinsed with methanol. The filtrate was concentrated under reduced pressure and dried under high vacuum to provide 2-[6-amino-5-(methyloxy)-2,3-dihydro-1H-indol-1-yl]-N,N-dimethylacetamide. This was then carried forward without any further purification.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:25]=[CH:24][C:23]([S:20]([NH:19][C@@H:14]3[CH2:15][CH2:16][CH2:17][C:18]4[C:9]([O:8][CH2:7][C:6]([OH:36])=[O:5])=[CH:10][CH:11]=[CH:12][C:13]3=4)(=[O:22])=[O:21])=[CH:28][CH:27]=2)=[CH:30][CH:31]=1
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)N[C@@H]3CCCc4c(OCC(=O)OC(C)(C)C)cccc43)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2ccc(S(=O)(=O)N[C@@H]3CCCc4c(OCC(=O)O)cccc43)cc2)cc1
Yield: 9.5 %

Procedure:
The crude [(R)-5-(4′-methyl-biphenyl-4-sulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester was treated with 10% trifluoroacetic acid (0.02 mL) in dichloromethane (1 mL) at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase HPLC (Pursuit C-18, 20×150 mm, water/acetonitrile/0.05% trifluoroacetic acid) to give [(R)-5-(4′-methyl-biphenyl-4-sulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid (4.3 mg, 9.5% over two steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.02 (br. s, 1H), 8.13 (d, J=8.5 Hz, 1H), 7.78-8.00 (m, 4H), 7.68 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.03 (t, J=7.9 Hz, 1H), 6.73 (d, J=7.9 Hz, 1H), 6.66 (d, J=7.9 Hz, 1H), 4.62 (s, 2H), 4.29-4.44 (m, 1H), 2.42-2.62 (m, 2H), 2.37 (s, 3H), 1.79 (br. s, 1H), 1.56 (d, 3H); MS cald. for C25H25NO5S 451, obsd. 452 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23]C(=O)OC(C)(C)C)[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:31])=[CH:4][N:3]=1.[ClH:32]>O1CCOCC1>[ClH:1].[ClH:32].[NH2:23][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][C:11]2[CH:10]=[C:9]([NH:8][C:6]3[C:5]([Cl:31])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:14]=[CH:13][CH:12]=2)[CH:22]=[CH:21][N:20]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)ccn1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a mixture of tert-butyl [4-(2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-2-yl]carbamate (128 mg, 0.28 mmol) in 1,4-dioxane (0.64 mL) was added 4 M of hydrogen chloride in 1,4-dioxane (3.0 mL). The resultant reaction mixture was stirred at rt for 2 hours. The reaction mixture was concentrated under vacuum to give the desired product (120 mg, 100%) as a very hygroscopic off-white powder. LCMS for C17H16Cl2N5 (M+H)+: m/z=360.0
Reaction SMILES: Cl[C:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][CH3:11])=[N:5][S:4][N:3]=1.C[Si]([N-:16][Si](C)(C)C)(C)C.[Na+].Cl.[OH-].[Na+]>C1COCC1>[NH2:16][C:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][CH3:11])=[N:5][S:4][N:3]=1
Reactant: CCCCSc1nsnc1Cl
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCSc1nsnc1N
Temperature: 0 °C
Yield: 82 %

Procedure:
A 1.04 g sample of 3-chloro-4-butylthio-1,2,5-thiadiazole was dissolved in 20 mL of THF and added to a 50 mL reaction vessel. The mixture was cooled to 0° C. A 10 mL sample of sodium bis(trimethylsilyl)amide in THF (1.0M) was added dropwise to the reaction vessel. The mixture was stirred at 0° C. The reaction was quenched using 50 mL water upon desired completion of reaction. The pH of the mixture was adjusted to 2.0 using HCl. The mixture was stirred for 15 min. and then adjusted to pH=11 using NaOH. The mixture was extracted using ether. The organic layers were combined, dried, and filtered. The filtrate was concentrated to dryness. The resulting product was purified using column chromatography. Yield: 1.07 g (65%). The N,N-bis(trimethylsilyl)-3-amino-4-butylthio-1,2,5-thiadiazole was suspended in 3N HCl and heated to about 50° C. The mixture was stirred for 3 h. The pH was adjusted to 11 using NaOH. The mixture was extracted using t-butylmethyl ester. The organics were combined, dried, filtered and concentrated to dryness. Yield: 0.43 g (45%). (Compound 66). The process substantially as described was repeated to yield 82% of the desired 3-amino-4-butylthio-1,2,5-thiadiazole.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH:44]1CC[S:46](=[O:50])(=[O:49])[CH2:45]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH:14]3[CH2:44][CH2:45][S:46](=[O:50])(=[O:49])[CH2:15]3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S1(=O)CCC(Br)C1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(C3CCS(=O)(=O)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-bromo-tetrahydro-thiophene 1,1-di oxide and isolated as white solid. MS (m/e): 401.3 (MH+).
Reaction SMILES: [C:1]([O:9][CH:10]([C:14](=O)[CH3:15])[C:11](=O)[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][NH:18][NH2:19]>C(O)C>[C:1]([O:9][C:10]1[C:14]([CH3:15])=[N:19][N:18]([CH3:17])[C:11]=1[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(OC(=O)c1ccccc1)C(C)=O
Reactant: CNN
Solvent: CCO
Product: Cc1nn(C)c(C)c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
A flask was charged with 2,4-dioxopentan-3-yl benzoate (82.59 g, 375.0 mmol) and ethanol (1.5 L) was added. Methylhydrazine (39.90 ml, 750.1 mmol) in ethanol (150 mL) was added, and the reaction was stirred at ambient temperature for 2 hours, then concentrated in vacuo to afford 1,3,5-trimethyl-1H-pyrazol-4-yl benzoate (80 g, 92.6% yield).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28](CC3C=CC(OC)=CC=3)[S:29]([CH3:32])(=[O:31])=[O:30])[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1>C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)S(C)(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1cc(N[C@H]2CC[C@H](N)CC2)nn2c(C(=O)Nc3ccncc3F)cnc12
Temperature: 80 °C

Procedure:
A mixture of 6-(trans-4-aminocyclohexylamino)-N-(3-fluoropyridin-4-yl)-8-(N-(4-methoxybenzyl)methylsulfonamido)imidazo[1,2-b]pyridazine-3-carboxamide (30 mg, 0.037 mmol) in TFA (1 mL) was heated to 80° C. for 1.5 h. The reaction mixture was concentrated and evaporated from DCM/MeOH to give 20B (26 mg, 102%) as a white solid. [M+H]=463. HPLC Peak Rt=1.758 minutes. (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm.)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1ccc(F)cc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)cc1Br

Procedure:
A suspension of 2-bromo-4-fluorobenzoic acid (6.87 g, 31.37 mmol) in dichloromethane (70 mL) containing a few drops of dimethylformamide was treated dropwise under nitrogen with a 2M solution of oxalyl chloride in dichloromethane (1.16 equivalents). After gas evolution subsided, the reaction mixture was refluxed for an additional 25 minutes and then the solution was evaporated to dryness in vacuo. The crude acid chloride was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[Cl:39])[O:5][C:6]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([NH:18][CH:19]([CH3:34])[CH2:20][CH2:21][CH2:22][N:23]2C(=O)C3=CC=CC=C3C2=O)=[C:12]2[C:7]=1[C:8]([CH3:35])=[CH:9][CH:10]=[N:11]2>C(O)C>[NH2:23][CH2:22][CH2:21][CH2:20][CH:19]([NH:18][C:13]1[CH:14]=[C:15]([O:16][CH3:17])[C:6]([O:5][C:4]2[CH:36]=[CH:37][C:38]([Cl:39])=[C:2]([Cl:1])[CH:3]=2)=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[CH3:35])[CH3:34]
Reactant: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1Oc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: COc1cc(NC(C)CCCN)c2nccc(C)c2c1Oc1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 12.2 g of 5-(3,4-dichlorophenoxy)-6-methoxy-4-methyl-8-[(4-phthalimido-1methylbutyl)amino]quinoline (21.6 mM) and 4 ml of 98% hydrazene hydrate in 500 ml of ethanol was refluxed 5 hours. The reaction mixture was evaporated under vacuum and the residue was partitioned between 400 ml of 10% potassium hydroxide and 400 ml of ethyl acetate. The organic layer was washed twice with 300 ml of 10% potassium hydroxide then four times with water, dried with anhydrous sodium sulfate and evaporated. The residue was used in the next reaction with out further purification.