Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([OH:10])=O.[NH2:11][CH2:12][CH2:13][NH:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([NH:11][CH2:12][CH2:13][NH:14][C:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:10]
Reactant: Cn1ncc(C(=O)O)c1N
Reactant: NCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1ncc(C(=O)NCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
To a solution of 5-amino-1-methyl-1H-pyrazole-4-carboxylic acid (7.1 g), N-(2-aminoethyl)tritylamine (15.1 g) and triethylamine (10.1 g) in chloroform (200 ml) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (9.6 g), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate and dried in vacuo to give 5-amino-1-methyl-N-[2-(tritylamino)ethyl]-1H-pyrazole-4-carboxamide (11.4 g) as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9](=O)[CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([CH3:4])([CH3:3])[CH3:2].[C:21]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH2:24][CH3:25])=[O:22]>C1C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[CH:26]=[C:9]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C=C(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
To a solution of (3-tert-Butoxycarbonylamino-2-oxo-propyl)-carbamic acid tert-butyl ester (28 g, 97.0 mmol) dissolved in benzene (350 ml) was added (carbethoxymethylene)-triphenyl phosphorane (89 g, 0.26 mol) and the reaction mixture stirred for 16 hours at 45° C., under a N2 atmosphere. The mixture was concentrated and purified by column chromatography on silica gel (ethyl acetate:hexane, 1:3, v/v) to afford the product as a yellowish solid (26 g, 75%). 1H NMR (CDCl3) δ 1.43 (s, 18H), 1.59 (s, 3H), 3.90 (d, 2H, J=4.75 Hz), 4.11 (m, 4H), 5.35 (m, 2H), 5.87 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[NH:14][N:15]=[CH:16][C:11]3=[C:10]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:9]=2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)=[C:10]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:11]3[C:12](=[N:14][N:15]([CH2:29][CH2:30][CH2:31][O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)[CH:16]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOC1CCCCO1
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccco3)c2-c2ccncc2)cc1
Product: Fc1ccc(-c2nc3nn(CCCOC4CCCCO4)cc3c(-c3ccco3)c2-c2ccncc2)cc1

Procedure:
Following a similar procedure to that described in examples 6 and 7, but starting from 6-(4-fluorophenyl)-4-(2-furyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (obtained in example 171) and 2-(3-bromopropoxy)tetrahydropyran, the desired compound was obtained.
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH2:18]([N:25]1[C:33]2[C:32]([N:34]3[CH2:43][CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35]3)=[CH:31][N:30]=[CH:29][C:28]=2[C:27]([CH3:44])=[C:26]1[CH3:45])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH2:46]>C(O)(=O)C>[CH2:18]([N:25]1[C:33]2[C:32]([N:34]3[CH2:43][CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35]3)=[CH:31][N:30]=[CH:29][C:28]=2[C:27]([CH2:44][OH:46])=[C:26]1[CH3:45])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)cncc12
Reactant: O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: CC(=O)O
Product: Cc1c(CO)c2cncc(N3CCc4ccccc4C3)c2n1Cc1ccccc1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
The compound (250.4 mg, 0.62 mmol) prepared in Example 35 was treated with a saturated sodium bicarbonate solution to obtain 1-benzyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[3,2-c]pyridine (216.8 mg, 0.59 mmol). A mmonium cerium (IV) nitrate (973 mg, 1.77 mmol) was added at room temperature to a solution of 1-benzyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[3,2-c]pyridine (216.8 mg, 0.59 mmol) in acetic acid (3 ml) and then stirred for 4 hours at 55° C. The reaction mixture was cooled to room temperature, added to water, and then extracted with ethyl acetate. The separated organic layer was washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in methanol (10 ml). 2N Lithium hydroxide (2.5 ml) was added to the reaction mixture, which was then stirred for 1 hour at room temperature. The reaction mixture was neutralized with IN hydrochloride, concentrated under reduced pressure, and then extracted with ethyl acetate. The separated organic layer was dried on anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography to give 1-benzyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-3-hydroxymethyl-2-methyl-1H -pyrrolo[3,2-c]pyridine, which was then dissolved in 10 ml of ethyl acetate and saturated with hydrochloric acid gas. The resulting precipitate was filtered to give the titled compound as a white solid (200 mg, 76.8%).
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[CH:22]=[CH:21][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.C(=O)([O-])[O-].[K+].[K+].O.[C:30]1([CH2:36][CH2:37][C:38](Cl)=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[N:3]1([C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([NH:20][C:38](=[O:39])[CH2:37][CH2:36][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:21][CH:22]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CCc1ccccc1)NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[4-(1H-Imidazol-1-yl)benzoyl]-4-piperidinamine dihydrochloride (4.46 g, 13.0 mmol) and potassium carbonate (6.67 g, 52.0 mmol) are dissolved in methylene chloride (60 mL) and water (30 mL) and the mixture is cooled with an ice bath. A solution of 3-phenylpropionyl chloride (2.72 g, 16.2 mmol) in methylene chloride (15 mL) is added dropwise over 15 min, and the mixture is stirred at room temperature for 2 hr. The phases are separated, and the organic phase is washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and evaporated. Chromatography of the residue on silica gel followed by recrystallization from acetonitrile affords the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[C:21]([C:23]2[CH:24]=[N:25][C:26]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:27][CH:28]=2)[CH:20]=[CH:19][C:18]=1[OH:36]>O1CCOCC1.N1C=CC=CC=1.CN(C1C=CN=CC=1)C.[OH-].[Na+]>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:36][C:18]1[CH:19]=[CH:20][C:21]([C:23]2[CH:24]=[N:25][C:26]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:27][CH:28]=2)=[CH:22][C:17]=1[F:16]
Reactant: Oc1ccc(-c2cnc(Nc3ccccc3)nc2)cc1F
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1cc2nccc(Oc3ccc(-c4cnc(Nc5ccccc5)nc4)cc3F)c2cc1OC
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline (0.064 g, 0.28 mmol) and 2-fluoro-4-(2-(phenylamino)pyrimidin-5-yl)phenol (Step 3, 0.48 g, 0.17 mmol) in dioxane (1.0 mL) and pyridine (0.5 mL) was treated with a catalytic amount of DMAP (0.12 g, 0.1 mmol). The mixture was heated under microwave irradiation at 180° C. for 30 min. After cooling to RT, the mixture was diluted with NaOH (0.2 N, 6 mL), and the suspension was filtered. The resulting solid was further purified on silica with 0-5% (NH3-MeOH in DCM) to afford the title compound as a white solid. MS (ESI pos. ion) m/z: 469. Calc'd for C27H21FN4O3: 468.16.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[C@H:16]([CH3:17])[S:15][CH2:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.Cl>C(Cl)Cl>[CH3:17][C@H:16]1[C:9]2[C:8]([N:7]3[CH2:6][CH2:5][NH:4][CH2:3][C@@H:2]3[CH3:1])=[N:13][CH:12]=[N:11][C:10]=2[CH2:14][S:15]1
Reactant: C[C@@H]1SCc2ncnc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)c21
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1SCc2ncnc(N3CCNC[C@@H]3C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 139.9 %

Procedure:
To a solution of (S)-tert-butyl 3-methyl-4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (2 g, 5.71 mmol) in DCM (20 mL) was added HCl (4M in dioxane, 6 mL). The mixture was stirred at room temperature overnight. The solvent was removed to afford (S)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine (2.0 g, 99%). MS (APCI+) [M+H]+ 251.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12](C(OC(C)(C)C)=O)=[C:11]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[N:10]([CH3:34])[N:9]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.[Cl-].[NH4+]>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:12]=[C:11]([NH:20][S:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:28][CH:29]=2)(=[O:22])=[O:23])[N:10]([CH3:34])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOc1nn(C)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCCOc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n(C)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To tert-butyl 3-[2-(acetyloxy)ethoxy]-5-({[4-(tert-butyl)phenyl]sulfonyl}amino)-1-methyl-1H-pyrazole-4-carboxylate (Preparation 9) (1.48 g) in dichloromethane (20 ml) was added trifluoroacetic acid (10 ml), at room temperature. The reaction mixture was stirred at room temperature for 2.5 hours and then refluxed for 3 hours. The reaction mixture was then diluted with a saturated solution of aqueous ammonium chloride (20 ml), and the aqueous was then extracted with ethyl acetate (2×20 ml). The organics were dried with magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by chromatography on a suction column packed with silica eluted with ethyl acetate:hexane (3:5) to yield the desired product as an off white solid (200 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([N:23]4[CH2:27][CH2:26][C@@H:25]([CH2:28][NH2:29])[CH2:24]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C1COCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([N:23]4[CH2:27][CH2:26][C@@H:25]([CH2:28][NH:29][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:24]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: NC[C@@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC[C@@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under N2, to a solution of (S)-(1-(7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-yl)pyrrolidin-3-yl)methanamine (Compound 77, 51 mg, 0.13 mmol) and Et3N (0.04 mL, 0.26 mmol) in anhydrous THF (3 mL) was added MsCl (30 mg, 0.26 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 0.5 hour, then quenched with H2O and extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography to afford the title compound. MS (m/z): 469 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([O:6][CH2:7][CH2:8][N:9]2[S:12]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])(=[O:14])=[O:13])=[N:4][CH:3]=1.C(N(CC)CC)C.[C:31]([O:34][CH2:35][CH3:36])(=[O:33])C>C(O)C>[CH2:35]([O:34][C:31]([C:2]1[CH:11]=[C:10]2[C:5]([O:6][CH2:7][CH2:8][N:9]2[S:12]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])(=[O:14])=[O:13])=[N:4][CH:3]=1)=[O:33])[CH3:36]
Reactant: CCOC(C)=O
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ncc(Br)cc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2
Yield: 67 %

Procedure:
A solution of 7-bromo-1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene (200 mg, 0.476 mmol), triethylamine (120 mg, 1.19 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane complex (19 mg, 29 μmol) in ethanol (2 mL) and ethyl acetate (2 mL) was heated at 110° C. under a carbon monoxide atmosphere (70 bar) for 20 h. The reaction mixture was evaporated and the residue chromatographed (SiO2, toluene-acetonitrile gradient) to produce 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carboxylic acid ethyl ester (132 mg, 67%). Off-white solid, MS (ISP)=413.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:32]>N1C=CC=CC=1>[NH2:1][C:2]1[NH:3][C:4](=[S:32])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(=S)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 135 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of 75 (1 g, 2.26 mmol) in pyridine (50 mL) was added at room temperature P2S5 (2.13 g, 4.79 mmol). The solution was refluxed gently (bath temperature 130-140° C.) for 29 h. The reaction mixture was evaporated to dryness in vacuo. The excess P2S5 was decomposed by the addition of H2O (40 mL) at 60° C. The mixture was stirred for 1 h at 60° C. and then cooled to room temperature. The mixture was extracted with CHCl3 (3×40 mL). The dried (MgSO4) organic layer was evaporated to yield a syrup, which was purified by flash column chromatography (silica, acetone/CHCl3=15%) to afford 0.93 g (90%) of 88 as a yellow solid: 1H (400 MHz, d6-DMSO) δ 12.50 (s, 1H), 7.35 (br s, 2H), 5.89 (m, 2H), 5.51 (t, J=6.4 Hz, 1H), 4.36 (dd, J=12.0, 4.0 Hz, 1H), 4.24 (m, 1H), 4.10 (q, J=6.0 Hz, 1H), 2.07 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H); MS (+)-ES [M+H]+ m/z 459.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.[NH2:19][NH2:20].CO>>[NH:19]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12)[NH2:20]
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Reactant: NN
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(NN)ccnc21
Temperature: 97 °C
Yield: 92 %

Procedure:
To 4-bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (1.98 g, 0.00605 mol) was added hydrazine (11.0 mL, 0.350 mol) followed by addition of methanol (1.0 mL, 0.025 mol) (to improve solubility). The reaction mixture was heated in a sealed tube at 97° C. (an oil bath) for 18 h. The reaction mixture was cooled to rt and formed an off-white solid precipitate. The solid was filtered off and rinsed with cold water and dried to give 4-hydrazino-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (1.55 gm) as a light yellow solid, LC/MS (M+H)+:279, 1H NMR (DMSO-d6) δ 7.98(d, 1H), 7.91(s, 1H), 7.28(d, 1H), 6.69(s, 1H), 6.61(d, 1H), 5.58(s, 2H), 4.37(s, 2H), 3.56(t, 2H), 0.90(t, 2H), 0.0(s, 9H).
Reaction SMILES: Cl[Sn]Cl.O.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][N:17]=[N:16][CH:15]=2)=[CH:10][CH:9]=1)([O-])=O.C([O-])(O)=O.[Na+]>CCO>[S:18]1[C:14]([C:11]2[CH:10]=[CH:9][C:8]([NH2:5])=[CH:13][CH:12]=2)=[CH:15][N:16]=[N:17]1
Reactant: O=[N+]([O-])c1ccc(-c2cnns2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2cnns2)cc1
Temperature: 70 °C
Yield: 94.7 %

Procedure:
SnCl2.H2O (3.21 g, 5 eq) was added to a slurry of (5-(4-Nitrophenyl)-1,2,3-thiadiazole (Lancaster Synthesis) (0.59 g, 2.8 mmol) in absolute EtOH (50 mL) and the reaction heated to 70° C. for 2 h. The reaction was allowed to cool to room temperature and pour into saturated NaHCO3 and ice. The product was extracted with EtOAc (2×) the solution dried (MgSO4) and evaporated to dryness in vacuo to yield 0.47 g of a light yellow solid mp 126-128° C.
Reaction SMILES: S(=O)(=O)(O)O.CO.[CH3:8][C:9](=[CH2:18])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH3:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[CH3:26]>O>[CH3:19][C:20]1[CH:21]=[C:22]([C:9]([CH3:18])([CH3:8])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:23]=[CH:24][C:25]=1[CH3:26]
Reactant: C=C(C)CCCCC(=O)OC
Reactant: Cc1ccccc1C
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)CCCCC(C)(C)c1ccc(C)c(C)c1

Procedure:
300 parts of 98% sulfuric acid, 64 parts of methanol, 71 parts of methyl 5-methylhex-5-enecarboxylate and 53 parts of o-xylene are stirred at room temperature for 3 days and then poured into 2000 parts of water. This is followed by extraction with ether, washing of the extract with water and evaporation of the ether. The residue is dissolved in 500 parts of methanol, one part of p-toluenesulfonic acid, and the mixture is heated under reflux for 6 hours. The methanol is then distilled off, and the residue is taken up in ether and washed first with aqueous sodium bicarbonate and then with water. The ether is evaporated off and the residue is distilled to give methyl 5-(3,4-dimethylphenyl)-5-methylhexanecarboxylate having a boiling point of 176°-182° C./16 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][CH2:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[Cl:10][CH2:11][S:12]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[Cl:1])(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)CCl
Reactant: Nc1ccc(F)cc1Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S(=O)(CCl)Nc1ccc(F)cc1Cl
Temperature: 7.5 °C
Yield: 75 %

Procedure:
72.8 g (0.5 mol) of 2-chloro-4-fluoroaniline were dissolved in 400 mL of toluene and cooled to 5-10° C., and then 79 g (0.53 mol) of chloromethylsulfonyl chloride were added slowly with stirring. The temperature was kept below 10-15° C. The mixture was then heated to 40° C. for 30 minutes and cooled again to 5-10° C. At this temperature, 101 g (1 mol) of triethylamine was added with stirring and cooling. After the addition was complete, the mixture was stirred at 40° C. for an additional 8 hours and then poured into 1050 mL of 6 N hydrochloric acid. The organic phase was separated and the aqueous phase was washed with toluene. The combined organic phases were poured with vigorous stirring into 12.5% sodium hydroxide solution. The basic aqueous phase was separated and the organic phase was washed with aqueous sodium hydroxide solution. The combined aqueous phases were treated with active carbon and filtered. 6 N hydrochloric acid was added with cooling until the pH was below 7. The precipitated product was filtered off, washed with water and dried to yield 96.8 g (75%) of the title compound as a solid melting at 83-85° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:23][C:24]1[C:31]([NH:32][C:33]2[NH:59][C:36]3=[N:37][C:38]([O:54][CH2:55][CH:56]([F:58])[F:57])=[C:39]([C:41](=[O:53])[NH:42][C@H:43]4[CH2:48][CH2:47][C@H:46]([C:49]([F:52])([F:51])[F:50])[CH2:45][CH2:44]4)[CH:40]=[C:35]3[N:34]=2)=[C:30]([Cl:60])[CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27].CCN(C(C)C)C(C)C.[F:70][C:71]([CH3:76])([CH3:75])[C:72](O)=[O:73]>CN(C=O)C>[Cl:23][C:24]1[C:31]([NH:32][C:33]2[NH:59][C:36]3=[N:37][C:38]([O:54][CH2:55][CH:56]([F:57])[F:58])=[C:39]([C:41](=[O:53])[NH:42][C@H:43]4[CH2:48][CH2:47][C@H:46]([C:49]([F:52])([F:50])[F:51])[CH2:45][CH2:44]4)[CH:40]=[C:35]3[N:34]=2)=[C:30]([Cl:60])[CH:29]=[CH:28][C:25]=1[CH2:26][NH:27][C:72](=[O:73])[C:71]([CH3:76])([F:70])[CH3:75]
Reactant: CC(C)(F)C(=O)O
Reactant: NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(OCC(F)F)nc3[nH]2)c1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(F)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(OCC(F)F)nc3[nH]2)c1Cl
Reaction time: 72 h

Procedure:
TBTU (1.0 ml of a 0.11 M solution in DMF) is added to a mixture of 2,4-dichloro-3-[6-(trans-4-trifluoromethyl-cyclohexylcarbamoyl)-5-(2,2-difluoro-ethoxy)-3H-imidazo[4,5-b]pyridin-2-ylamino]benzylamine (1.0 ml of a 0.10 M solution in DMF), DIPEA (52 μl, 0.3 mmol) and 2-fluoro-2-methylpropionic acid (1.0 ml of a 0.13 M solution in DMF) and it is stirred for 3 d and the mixture is purified by prep. HPLC.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:18])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:22](Br)[CH2:23][CH3:24].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:19])[N:7]([C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:18])[CH:14]=2)[CH2:9]1)[CH2:22][CH2:23][CH3:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2cc(Br)ccc2C1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(C(=O)OC(C)(C)C)[C@H]1CCc2cc(Br)ccc2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
((S)-6-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (12.2 g, 37.4 mmol) was dissolved in N,N-dimethylformamide (1000 ml). Sodium hydride (50% in oil) (1.975 g, 41.14 mmol) was added and the mixture was stirred for 15 minutes at room temperature. Propyl bromide (3.74 ml, 41.14 mmol) was added and the reaction mixture was stirred at room temperature over night. The reaction mixture was poured into a mixture of ice and H2O (400 ml) and extracted twice with 200 ml of diethyl ether. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness to yield 14.4 g of crude product. The crude product was purified by chromatography on silica gel using cyclohexane/ethyl acetate (95:5) as eluent, yielding the title compound (10.5 g, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])=[CH:11][C:10]=1[NH2:22])=[S:7])=[O:4].[CH3:23][O:24]C(NC(NC1C=CC(CCCC)=CC=1NC=O)=S)=O>>[CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][CH:19]([CH3:20])[CH3:21])=[O:17])=[CH:11][C:10]=1[NH:22][CH:23]=[O:24])=[S:7])=[O:4]
Reactant: COC(=O)NC(=S)Nc1ccc(NC(=O)OC(C)C)cc1N
Reactant: CCCCc1ccc(NC(=S)NC(=O)OC)c(NC=O)c1
Product: COC(=O)NC(=S)Nc1ccc(NC(=O)OC(C)C)cc1NC=O

Procedure:
By proceeding in a similar manner but substituting an equimolecular quantity of 1-methoxycarbonyl-3-(2-amino-4-isopropoxycarbonylaminophenyl)thiourea for the 1-methoxycarbonyl-3-(2-amino-4-n-butylphenyl)thiourea, there was obtained 1-methoxycarbonyl-3-(2-formamido-4-isopropoxycarbonylaminophenyl)thiourea, m.p. 194°-195° C. (with decomposition).