Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@H:8](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:7][CH2:6]2.[N-:30]=[N+:31]=[N-:32].[Na+].C1OCCOCCOCCOCCOC1>CN(C)C=O>[N:30]([C@H:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)CC[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@@H]2c1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CC[C@H](N=[N+]=[N-])[C@@H]2c1ccccc1
Temperature: 0 °C
Yield: 58.1 %

Procedure:
A N,N-dimethylformamide solution (50 mL) of crude trans-6-methoxy-1-phenyl-2-(4-methylbenzenesulfonyl)oxy-1,2,3,4-tetrahydronaphthalene 30 (3.4 g), sodium azide (3.78 g, 58.3 mmol) and 15-crown-5 (6.61 mL, 33.2 mmol) was heated at 75° C. for 7 h. The reaction mixture was poured into ice water (200 mL), and the product was extracted into diethyl ether (3×50 mL). The organic extracts were combined and washed successively with water (4×100 mL) and a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. The solvent was evaporated in vacuo, and the remaining residue was purified by medium pressure chromatography using 3% ethyl acetate in hexanes as the eluent to give crude cis-2-azido-6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalene 31 (1.35 g, ~62%) as an oil which was used without further purification in the subsequent step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Br:11]Br>O>[Br:11][C:7]1[CH:6]=[N:5][CH:4]=[C:3]([N+:8]([O-:10])=[O:9])[C:2]=1[OH:1]
Reactant: BrBr
Reactant: O=[N+]([O-])c1cnccc1O
Solvent: O
Product: O=[N+]([O-])c1cncc(Br)c1O
Temperature: 50 °C
Yield: 79.8 %

Procedure:
4-hydroxy-3-nitropyridine (40 g, 0.285 mol) was added to 200 ml of water and then bromine (18.44 ml, 0.36 mol) was slowly added thereto at room temperature. The reaction mixture was stirred under heating for 2 hours at 50° C. and then cooled to room temperature. The resulting precipitate was filtered, washed with water, and then dried to give the titled compound as a pale yellow solid (49.8 g, 87.8%). The product was used in the subsequent step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O.CCOCC.CCCCCC>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(N)c(Br)c1

Procedure:
To a stirred solution of 48.96 g 4'-aminoacetophenone in 490 ml of toluene was added 64.5 g of solid N-bromosuccinimide in portions over 30 minutes, such that the temperature did not exceed 40° C. Fifteen minutes later, the warm solution was washed with water, dried with sodium sulfate and evaporated in vacuo, giving a dark brown oil, which became crystalline when treated with 20 ml of ether and 80 ml of hexane. The brown crystals were collected, giving 70.5 g of the desired compound, mp 59°-62° C.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.ClC1C=CC=CC=1C(O)C1C=CC(Cl)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([OH:7])[C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: OC(c1ccc(Cl)cc1)c1ccccc1Cl
Product: OC(c1ccc(Br)cc1)c1ccc(Br)cc1

Procedure:
This material was prepared from 4,4′-dibromobenzophenone using the procedure described for compound (7) (9.67 g, 96%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OC([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:30]=2C(O)=O)[CH2:24][CH2:23]1)=O)(C)(C)C.NC1C=CC=C(Cl)C=1C(O)=O.C([O:54][C:55]([N:57]1CCC(=O)CC1)=O)(C)(C)C>ClC(Cl)C>[Cl:38][C:34]1[C:30]2[NH:57][C:55](=[O:54])[N:28]([CH:25]3[CH2:24][CH2:23][NH:22][CH2:27][CH2:26]3)[C:29]=2[CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(Cl)c2C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Nc1cccc(Cl)c1C(=O)O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=c1[nH]c2c(Cl)cccc2n1C1CCNCC1
Reaction time: 5 h

Procedure:
2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]amino}-6-chlorobenzoic acid Sodium triacetoxyborohydride (3.09 g, 14.6 mmol) was added to a solution of 2-amino-6-chlorobenzoic acid (1.00 g, 5.83 mmol) and N-(t-butoxycarbonyl)-4-piperidone (2.32 g, 11.7 mmol) in dichloroethane (20 mL) at room temperature. After 5 h, the reaction was quenched with saturated aqueous ammonium chloride. This mixture was separated and extracted with ethyl acetate (3×). After drying over sodium sulfate, the solution was filtered and evaporated to give the crude product. This was purified by chromatorgraphy (silica gel, 0 to 15% methanol in methylene chloride gradient elution), which gave the title compound contaminated with some ketone starting material (3.60 g). MS 335.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].C(N(CC)C(C)C)(C)C.C(OCC)C>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:10]([Br:9])[CH:11]=2)[CH:7]=1
Reactant: Nc1cccc(Br)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CCO
Product: Clc1cc(Nc2cccc(Br)c2)ncn1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
A solution of 4,6-dichloropyrimidine (5 g, 33.6 mmol), 3-bromoaniline (5.8 g, 33.7 mmol) and N,N-diisopropylethylamine (DMA) (5.2 g, 40.2 mmol) in ethanol (40 mL) was heated at 80° C. for 16 hr. The reaction mixture was cooled to ambient temperature, diethylether (35 mL) was added while the mixture was being stirred. The product was precipitated, filtered, washed with water and dried to afford 5.9 g (62% yield) of a light colored solid. MS (m/z): MH+=284, 286, 288.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([OH:12])[CH:5]=[CH:4][C:3]=1[C:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16].[C:19]([O:23][C:24](=[O:35])[NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]O)=[CH:29][CH:28]=1)([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[C:19]([O:23][C:24](=[O:35])[NH:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][O:12][C:6]2[CH:5]=[CH:4][C:3]([C:13](=[O:18])[CH2:14][CH:15]([CH3:16])[CH3:17])=[C:2]([OH:1])[C:7]=2[C:8]([F:9])([F:10])[F:11])=[CH:31][CH:32]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Reactant: CC(C)CC(=O)c1ccc(O)c(C(F)(F)F)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)CC(=O)c1ccc(OCc2ccc(CNC(=O)OC(C)(C)C)cc2)c(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
Mix 1-(2,4-dihydroxy-3-trifluoromethyl-phenyl)-3-methyl-butan-1-one (2 g, 7.63 mmol), (4-hydroxymethyl-benzyl)-carbamic acid tert-butyl ester (1.99 g, 8.39 mmol) and triphenylphosphine (2.20 g, 8.39 mmol) in anhydrous toluene (125 mL) at room temperature under argon gas. Slowly add diisopropyl azodicarboxylate (1.70 g, 8.39 mmol, 1.7 mL) over 30 min. Stir the reaction mixture at room temperature overnight. Concentrate the mixture under reduced pressure and purify the residue by flash chromatography (silica gel) eluting with using 25% ethyl acetate/hexane to provide the product as a white solid (1.5 g, 3.12 mmol, 41% yield). MS (m/z): 480 (M−1).
Reaction SMILES: C([O:8][NH:9][C:10](=[O:42])[C@H:11]([N:18]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]2[O:39][CH2:40][O:41][C:35]=2[CH:34]=1)[S:19]([C:22]1[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH3:30])=[CH:24][C:23]=1[CH3:31])(=[O:21])=[O:20])[CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])C1C=CC=CC=1>[Pd].C(O)C.O1CCCC1>[OH:8][NH:9][C:10](=[O:42])[C@H:11]([N:18]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]2[O:39][CH2:40][O:41][C:35]=2[CH:34]=1)[S:19]([C:22]1[C:23]([CH3:31])=[CH:24][C:25]([O:29][CH3:30])=[CH:26][C:27]=1[CH3:28])(=[O:20])=[O:21])[CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNS(C)(=O)=O)C(=O)NOCc2ccccc2)c(C)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNS(C)(=O)=O)C(=O)NO)c(C)c1
Reaction time: 6 h
Yield: 44.8 %

Procedure:
To a solution of N-benzyloxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionamide (580 mg, 0.94 mmol) in a 3:1 mixture of ethanol/tetrahydrofuran (30 ml) was added 10% palladium on charcoal (60 mg). The reaction mixture was placed under a hydrogen balloon and stirred for 6 hours. The material was filtered through a short plug of silica, rinsing with ethanol (200 ml). The filtrate was condensed on the roto-evaporator and the residue was purified by preparative thin layer chromatography using 8.5% methanol-methylene chloride as eluant providing N-hydroxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionamide as a tan powder (223 mg).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]2=[O:20])=[CH:7][CH:6]=1)=[O:3].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:23]=1>>[CH3:18][C:14]1([CH3:19])[CH2:15][C:16](=[O:17])[N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:33][CH2:34][N:29]([CH2:28][C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH2:30][CH2:31]3)=[O:3])=[CH:6][CH:7]=2)[C:12](=[O:20])[CH2:13]1
Reactant: c1cncc(CN2CCNCC2)c1
Reactant: CC1(C)CC(=O)N(c2ccc(OC(=O)Cl)cc2)C(=O)C1
Agent: Cl
Product: CC1(C)CC(=O)N(c2ccc(OC(=O)N3CCN(Cc4cccnc4)CC3)cc2)C(=O)C1

Procedure:
The title compound was prepared from 4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-phenyl chloroformate and 1-pyridin-3-ylmethyl-piperazine, hydrochloride, preparative HPLC (Method C) (75%, colourless oil). HPLC-MS m/z=437.2 (M+1), Rt: 1.70 min.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10].CS(C)=O.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH:19]=[O:20])(=[O:11])=[O:10]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2c(C)nn(C)c2Cl)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2c(C)nn(C)c2Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
To 227 mg (0.660 mmol) of 3-[3-(5-chloro-1,3-dimethyl-pyrazole-4-sulfonyloxy)-5-methylphenoxy]propanol, as prepared in the preceding step, in dichloromethane (2 mL) containing 61 μL (0.79 mmol) of anhydrous dimethyl sulfoxide and 275 μL (1.58 mmol) of N,N-diisopropylethylamine was added 124 mg (0.78 mmol) of sulfur trioxide pyridine complex. The reaction mixture was stirred at ambient temperature for 60 min and then purified by flash chromatography (dichloromethane then 20% ethyl acetate/dichloromethane) to give 75 mg of the title compound as an unstable oil. TLC clearly showed 3-(5-chloro-1,3-dimethylpyrazole-4-sulfonyloxy)-5-methylphenol as the major byproduct. 1H-NMR (300 MHz, CDCl3) δ 9.85 (t, 1H, J=1.5 Hz), 6.64 (s, 1H), 6.51-6.57 (m, 2H), 6.46 (t, 1H, J=2 Hz), 6.42 (t, 1H, J=2 Hz), 4.23 (t, 2H, J=6 Hz), 3.82 (s, 3H), 2.89 (td, 2H, J=1, 6 Hz), 2.29 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: [C:1]1([C@@H:13]2[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14]2)[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3][N:2]=1.Cl[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CCO>[C:1]1([C@@H:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=3)[CH2:14]2)[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3][N:2]=1
Reactant: NC1CC[C@@H](c2n[nH]c3cnc4[nH]ccc4c23)C1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N#Cc1ccc(N[C@@H]2CC[C@@H](c3n[nH]c4cnc5[nH]ccc5c34)C2)nc1
Yield: 4 %

Procedure:
(3R)-3-(3,6-Dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine (0.12 g, 0.48 mmol, Preparation #29), 6-chloronicotinonitrile (0.069 g, 0.48 mmol), and DIEA (0.13 mL, 0.75 mmol) were heated in EtOH (3.0 mL) at about 80° C. for about 10 h. The solvent was removed under reduced pressure and the crude material was purified by RP-HPLC (Table 2, Method h) to give 6-((1R,3R)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentylamino)nicotinonitrile (0.007, 4%): LC/MS (Table 2, Method a) Rt=1.86 min; m/z: 344 (M+H)+ and 6-((1R,3S)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentylamino)nicotinonitrile (0.009 g, 5%): LC/MS (Table 2, Method a) Rt=1.89 min; m/z: 344 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li][CH3:30].[Li+].[Br-].O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)([OH:16])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cccc(-c2ccccc2)n1)c1ccccc1OCc1ccccc1
Reactant: [Li]C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(c1cccc(-c2ccccc2)n1)c1ccccc1OCc1ccccc1
Temperature: -90 °C
Reaction time: 0.33 h
Yield: 98.3 %

Procedure:
To a solution of 11.7 g (32.0 mmol) of 17 in 260 mL of THF, 37 mL (33.6 mmol) of 0.91 M MeLi*LiBr in THF was added dropwise with vigorous stirring for 20 min at −90° C. The reaction mixture was slowly warmed to room temperature and 50 mL of water was added. The organic solvent was evaporated using a rotary evaporator. The crude product was extracted from the residue with 2×100 mL of dichloromethane. The combined extract was dried over Na2SO4 and then evaporated to dryness. This procedure gave 12.0 g (98%) of 18.
Reaction SMILES: CS[C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]=1.[CH3:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][O:28][CH2:29][C:30]([NH:32][NH2:33])=O)=[CH:25][CH:24]=1>CN(C)P(=O)(N(C)C)N(C)C>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][O:28][CH2:29][C:30]2[N:4]3[C:5]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:6]=4[C:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[N:8][CH2:9][C:3]3=[N:33][N:32]=2)=[CH:34][CH:35]=1
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: COc1ccc(COCC(=O)NN)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc(COCc2nnc3n2-c2ccc(Cl)cc2C(c2ccccc2)=NC3)cc1

Procedure:
A solution of 15,0 g 2-(methylthio)-5-phenyl-7-chloro-3H-1,4-benzodiazepine [cf. G. A. Archer et al., J. Org. Chem. 29, 231 (1964)] and 11,5 g 2-(p-methoxybenzyloxy)-acetic acid-hydrazide in 100 ml hexamethyl-phosphoric acid triamide is heated for 10 hours at 140°. The reaction mixture is worked up analogously to Example 1. The crude product is crystallised from ethyl acetate-petrol ether, whereby 1-[(p-methoxybenzyloxy)-methyl]-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine M.P. 157°-159° is obtained.
Reaction SMILES: C(OC([NH:8][C@@:9]1([CH3:37])[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27]([NH:29][NH:30][C:31]([S:33][CH3:34])=[S:32])=O)[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[C:10]1([CH3:36])[CH3:35])=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:8][C@@:9]1([CH3:37])[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27]4[S:32][C:31]([S:33][CH3:34])=[N:30][N:29]=4)[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21]([NH2:22])=[O:23])[C:10]1([CH3:35])[CH3:36]
Reactant: CSC(=S)NNC(=O)c1cc2c(N[C@@H]3CC[C@](C)(NC(=O)OC(C)(C)C)C3(C)C)c(C(N)=O)cnn2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CSc1nnc(-c2cc3c(N[C@@H]4CC[C@](C)(N)C4(C)C)c(C(N)=O)cnn3c2)s1
Yield: 208.2 %

Procedure:
A solution of methyl 2-(4-((1R,3S)-3-(tert-butoxycarbonylamino)-2,2,3-trimethylcyclopentylamino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carbonyl)hydrazinecarbodithioate (466.5 mg, 0.849 mmol) and p-toluenesulfonic acid monohydrate (404 mg, 2.122 mmol) in ethanol (4 mL) was heated to 120° C. for 50 minutes. The reaction mixture was concentrated to yield 4-(((1R,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-(5-(methylthio)-1,3,4-thiadiazol-2-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (763 mg, 94% yield). MS (ES+) m/z: 432.08 (M+H); HPLC retention time: 2.493 min (analytical HPLC Method F).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].O>O1CCCC1.ClCCl>[Si:6]([O:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[CH2:19][N:20]1[C:21](=[O:30])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]1=[O:29])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(CO)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under argon and at room temperature, imidazole (1.0 g, 15.0 mmol) and tert-butyldimethylsilyl chloride (1.7 g, 11.2 mmol) are added to a solution of 2-[3-(hydroxymethyl)benzyl]-1H-isoindole-1,3(2H)-dione (2.0 g, 7.5 mmol) in tetrahydrofuran (22.5 ml). The reaction mixture is stirred at room temperature for 16 h, and water is added. After addition of dichloromethane and phase separation, the aqueous phase is extracted with dichloromethane. The combined organic phases are dried (sodium sulfate), filtered and concentrated under reduced pressure. The desired product is purified by flash chromatography (petroleum ether/ethyl acetate mixtures). Yield: 2.7 g, 95% of theory.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH:11]2[CH2:15][N:14]([CH3:16])[CH2:13][CH:12]2[CH2:17][C:18]([O-:20])=O)=[CH:5][C:4]=1[O:21][CH3:22])[CH3:2].FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>>[CH2:1]([C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[C@@H:11]3[C@H:12]([CH2:17][C:18](=[O:20])[C:7]=2[C:8]=1[O:9][CH3:10])[CH2:13][N:14]([CH3:16])[CH2:15]3)[CH3:2]
Reactant: CCc1c(OC)cc(C2CN(C)CC2CC(=O)[O-])cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCc1c(OC)cc2c(c1OC)C(=O)C[C@@H]1CN(C)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.6 %

Procedure:
A mixture of 150 mg (0.41 mmol) of (4-(4-ethyl-3,5-dimethoxy-phenyl)-1-methyl-pyrrolidin-3-yl)-acetate, 1.5 ml trifluoroacetic acid and 0.15 ml of trifluoroacetic acid anhydride was stirred at room temperature over 2 hours. The reaction mixture was subsequently poured on to 50 ml of ice-water, made basic with 28% NaOH and extracted twice with 100 ml of methylene chloride each time. The combined organic phases were washed once with 50 ml of saturated sodium chloride solution, dried (MgSO4) and concentrated in a vacuum. The crude product obtained was purified by column chromatography on silica gel (methylene chloride/methanol/NH4OH 15:1:0.1). 15 mg (13%) of cis-7-ethyl-6,8-dimethoxy-2-methyl-1 ,2,3,3a,4,9b-hexahydro-benzo[e]isoindol-5-one were obtained as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[N:10]([CH2:25][CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9]1)(C)(C)C.[ClH:36]>O1CCOCC1>[ClH:36].[NH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([F:19])([F:18])[F:20])[C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[N:10]([CH2:25][CH2:26][O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(CCOCc2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CN(CCOCc2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O

Procedure:
In an analogous manner to that described in Example 1d), the treatment of the [(S)-5-(2-benzyloxy-ethyl)-2-oxo-1-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester with hydrochlorid acid (37%) in dioxane yielded the title compound as a light yellow foam; MS (m/e): 394 (M+H)+.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([OH:30])[CH:26]=4)[C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10]1)C)(C)(C)C.Cl[CH2:35][C:36]([NH:38][CH3:39])=[O:37].Cl>>[F:32][C:15]1[CH:16]=[C:17]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH2:35][C:36]([NH:38][CH3:39])=[O:37])[CH:26]=3)[C:21]2=[O:31])[CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][C@@H:9]([NH:7][CH3:6])[CH2:10]1
Reactant: CNC(=O)CCl
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2ccc(N3CCc4cc(O)ccc4C3=O)cc2F)C1
Agent: Cl
Product: CNC(=O)COc1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](NC)C3)c(F)c1)C2=O

Procedure:
According to Method K, {(R)-1-[2-fluoro-4-(6-hydroxy-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-pyrrolidin-3-yl}-methyl-carbamic acid tert-butyl ester was alkylated with 2-chloro-N-methyl-acetamide and the product was treated with hydrogen chloride (5 N in 2-propanol), releasing the amine. In this way the product was obtained with molecular weight 426.50 (C23H27FN4O3); MS (ESI): 427 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Cl[CH2:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:25][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:8]=1)=[O:6]
Reactant: ClCc1ncccn1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ncccn3)c3ccccc3c2=O)cc1C
Temperature: 80 °C
Yield: 44.1 %

Procedure:
Compound 4k was prepared following the procedure outlined in Step 3 of Example 1. Briefly described here, 97 mg (0.35 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one, 18 mg (0.45 mmol) of 60% sodium hydride and 66 mg (0.51 mmol) of 2-chloromethyl pyrimidine (prepared as described by Paine, J. B.; J. Het. Chem. 1987, 351) were combined in 1 mL N,N-dimethylformamide and heated at 80° C. for 2 h. The product was purified using reverse phase HPLC (mobile phase with a gradient 10-50% acetonitrile in 50 min), to give 57 mg of a pale yellow solid 4k as trifluoroacetate salt: LC-MSD, m/z for C23H19N3O2 [M+H]+=370.5, HPLC retention time: 2.4 min; 1H NMR (400 MHz, CDCl3): δ 2.3 (s, 3H), 2.35 (s, 3H), 5.6 (s, 2H), 7.15-7.2 (m, 1H), 7.25-7.3 (m, 1H), 7.4-7.5 (m, 1H), 7.5-7.55 (m, 1H), 7.6-7.7 (m, 3H), 8.4-8.5 (m, 2H), 8.7-8.75 (m, 2H).