Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[C:26]1(=O)[CH2:30][CH2:29][CH2:28][CH2:27]1.CS(Cl)(=O)=O.C(N(CC)CC)C>O1CCCC1.CCCCCC>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[C:26]1[CH2:30][CH2:29][CH2:28][CH:27]=1)[CH2:23][CH2:24][CH3:25]
Reactant: O=C1CCCC1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1=CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of diisopropylamine (2.97 ml, 21.2 mmol) in dry tetrahydrofuran (140 ml) is added n-butyllithium (1.4 M in hexane) (15.3 ml, 21.4 mmol) drop wise at 0° C. and the resulting mixture stirred for 30 min. To the reaction mixture is then added tributylstannane (6.2 ml, 23.1 mmol) and stirring is continued for 30 min at 0° C. before cooling to −78° C. Cyclopentanone (2.1 ml, 23.8 mmol) in tetrahydrofuran (10 ml) is added and stirring is continued for 1 h at −78° C. Methanesulfonyl chloride (7.4 ml, 96.0 mmol) and triethylamine (24.9 ml, 179 mmol) are added successively to the reaction mixture at −78° C. The temperature of the reaction mixture is slowly raised to room temperature over a period of 1 h. Hexane (300 ml) is added and partitioned with acetonitrile (100 ml). The combined hexane layers are washed with acetonitrile (2×100 ml) and evaporated to get the crude product. Column chromatography (silica gel, hexane) afforded tributyl-1-cyclopenten-1-yl-stannane (6.1 g, 17.1 mmol, 72%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=3)[NH:11][C:10]=2[OH:20])=[N:7][CH:8]=1)=O.[CH2:21]1[CH:25]2[CH2:26][NH:27][CH2:28][CH:24]2[CH2:23][O:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(OCC)(=O)C>[CH2:21]1[CH:25]2[CH2:26][N:27]([CH2:1][C:3]3[CH:4]=[CH:5][C:6]([C:9]4[C:17]5[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=5)[NH:11][C:10]=4[OH:20])=[N:7][CH:8]=3)[CH2:28][CH:24]2[CH2:23][O:22]1
Reactant: N#Cc1ccc2[nH]c(O)c(-c3ccc(C=O)cn3)c2c1
Reactant: C1NCC2COCC12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]c(O)c(-c3ccc(CN4CC5COCC5C4)cn3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42 %

Procedure:
164 mg of 3-(5-Formylpyridin-2-yl)-2-hydroxy-1H-indole-5-carbonitrile (0.62 mmol) from example 1.3 were dissolved in DMSO at 50° C. To this solution 134 mg (1.18 mmol) of hexahydro-1H-furo[3,4-c]pyrrole were added and the resulting deep-red solution was stirred at this temperature for 90 min. Afterwards 263 mg (1.24 mmol) of sodium triacetoxyborohydride were added and the mixture was stirred for 4 h and then cooled to RT followed by further stirring for 16 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with sat. NaHCO3 solution. The aqueous phase was re-extracted with ethyl acetate and the combined organic phases were washed with brine (5×), dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude was purified by flash chromatography (silica gel, DCM/MeOH) yielding a yellow solid. Amount 95 mg. Yield 42%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Si:7]([O:14][CH:15]([CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:16]([O:18][Si](C(C)(C)C)(C)C)=O)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].N1C=CC=CC=1.[NH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][N:40]=1>C(Cl)Cl.CN(C=O)C.O>[Si:7]([O:14][CH:15]([CH2:26][CH2:27][S:28]([CH3:31])(=[O:29])=[O:30])[C:16]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][N:40]=1)=[O:18])([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:8])[CH3:9]
Reactant: Cc1ccc(N)nc1
Reactant: CC(C)(C)[Si](C)(C)OC(=O)C(CCS(C)(=O)=O)O[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C(CCS(C)(=O)=O)O[Si](C)(C)C(C)(C)C)nc1
Reaction time: 1 h
Yield: 65.3 %

Procedure:
Oxalyl chloride (0.74 g, 5.84 mmol) in DCM (2 mL) was added slowly to a stirred solution of tert-butyl(dimethyl)silyl 2-{[tert-butyl(dimethyl)silyl]oxy}-4-(methylsulfonyl)butanoate (Step 2) (2.00 g, 4.87 mmol) in DCM (8 mL) and DMF (three drops). After 1 h at ambient temperature, gas evolution had subsided and the reaction mixture was concentrated in vacuo to remove excess oxalyl chloride. The residue was dissolved in DCM (8 mL) and pyridine (0.50 g, 6.33 mmol) and 2-amino-5-picoline (0.58 g, 5.36 mmol) were added. The reaction mixture was kept at ambient temperature for 1 h. Water was added and the two phases were separated. The aqueous phase was extracted with DCM. The organic extracts were combined and washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with DCM/EtOAc:10/1) to give the title compound as a colourless oil (1.23 g), 1H NMR (300 MHz, CDCl3) δ 8.92 (br s, 1H), 8.13 (d, 1H), 8.08 (d, 1H), 7.53 (dd, 1H), 4.44 (t, 1H), 3.19 (m, 1H), 3.05 (m, 1H), 2.90 (s, 3H), 2.44 (m, 1H), 2.28 (m, 4H), 0.97 (s, 9H), 0.19 (d, 6H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[I-].[Na+].C([O:14][CH2:15][C@H:16]1[C@@H:21]([S:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][CH2:19][CH2:18][O:17]1)C1C=CC=CC=1.C(#N)C>C(Cl)Cl.O>[CH2:23]([S:22][C@H:21]1[CH2:20][CH2:19][CH2:18][O:17][C@H:16]1[CH2:15][OH:14])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCCS[C@H]1CCCO[C@H]1COCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCS[C@H]1CCCO[C@H]1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.49 g of aluminum chloride, 7.29 g of sodium iodide and a solution of 2.250 g of dl-cis-2-benzyloxymethyl-3-hexadecylthiotetrahydropyran (prepared as described in Preparation 17) in 50 ml of methylene chloride were added, in that order, to a mixture of 100 ml of acetonitrile and 50 ml of methylene chloride. The reaction mixture was then stirred at room temperature for 2 hours, after which it was diluted with water, and filtered using a Celite (trade mark) filter aid. The filtrate was extracted with methylene chloride. The extract was washed with an aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride and dried. The extract was then concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through 50 g of silica gel. The fraction eluted with mixtures of ethyl acetate and hexane ranging from 1:9 to 1:3 by volume was collected to give 1.736 g of the title compound as white crystals, melting at 52°-53° C. (hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([F:16])([F:15])[F:14])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.C[CH2:22][N:23](C(C)C)C(C)C.CN>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([F:16])([F:15])[F:14])[N:5]=[C:4]([NH:23][CH3:22])[N:3]=1
Reactant: CS(=O)(=O)c1nc(Cl)cc(N2CCC[C@H]2C(F)(F)F)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: C1COCCO1
Product: CNc1nc(Cl)cc(N2CCC[C@H]2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
The crude 4-chloro-2-(methylsulfonyl)-6-[(2S)-2-(trifluoromethyl)-1-pyrrolidinyl]pyrimidine (1.09 g, 3.31 mmol) was dissolved 1,4-dioxane (30 mL). Hunig's base (2.88 mL, 16.53 mmol) and methylamine (6.61 mL, 13.22 mmol) were added, and the solution was stirred at room temperature overnight. Additional methylamine (2 mL) was added. The reaction was concentrated, then diluted with 30 mL EtOAc and washed with 0.1 N HCl (30 mL). The aqueous was back extracted with EtOAc and the organics were combined and washed with saturated NaCl, dried over MgSO4, filtered and concentrated. Purfication on Biotage 25 g SNAP column with a gradient of 0 to 50% EtOAc in Hexane over 35 minutes afforded the title compound (760 mg) as a clear oil. LC-MS (ES) m/z=281 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:39][O:40][C:41]1[CH:83]=[CH:82][C:44]([CH2:45][N:46]2[C:50]3=[N:51][CH:52]=[CH:53][C:54]([O:55][C:56]4[CH:61]=[CH:60][C:59]([NH2:62])=[CH:58][C:57]=4[F:63])=[C:49]3[C:48]([C:64]3[CH:65]=[N:66][N:67]([CH:69]4[CH2:74][CH2:73][N:72]([C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:71][CH2:70]4)[CH:68]=3)=[N:47]2)=[CH:43][CH:42]=1.CCN(C(C)C)C(C)C>O.CN(C=O)C>[F:63][C:57]1[CH:58]=[C:59]([NH:62][C:15]([C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10][CH:11]=2)=[O:17])[CH:60]=[CH:61][C:56]=1[O:55][C:54]1[CH:53]=[CH:52][N:51]=[C:50]2[N:46]([CH2:45][C:44]3[CH:43]=[CH:42][C:41]([O:40][CH3:39])=[CH:83][CH:82]=3)[N:47]=[C:48]([C:64]3[CH:65]=[N:66][N:67]([CH:69]4[CH2:74][CH2:73][N:72]([C:75]([O:77][C:78]([CH3:80])([CH3:81])[CH3:79])=[O:76])[CH2:71][CH2:70]4)[CH:68]=3)[C:49]=12
Reactant: COc1ccc(Cn2nc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(Cn2nc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 3.4 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (0.0840 g, 0.358 mmol obtained from Example 19, step C), EDCI (0.0687 g, 0.358 mmol), HOBT (0.0549 g, 0.358 mmol), and DMF (5 mL). The reaction mixture was stirred for 30 minute and tert-butyl 4-(4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.110 g, 0.179 mmol) and Hunig's base (0.0463 g, 0.358 mmol) were added. The reaction mixture was stirred for 18 hours, then diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was purified by preparative TLC (0.5 mm thickness) eluting with CHCl3/MeOH(NH3 7N) 4:1. To the isolated product was added TFA (2 mL) and the solution was heated to 70° C. for 1 hour. The solution was concentrated and triturated with DCM/MeOH 1:1. The solids were collected by filtration to provide 5.1 mg (5%) of the desired product. LRMS M+1 (610.0) observed.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([CH3:15])=[C:7]([CH3:14])[C:8]=1[C:9](OCC)=O)[CH2:2][CH3:3].[CH3:16]C1OC(C)OC(C)O1>>[CH2:1]([C:4]1[NH:5][C:6]([CH3:15])=[C:7]([CH3:14])[C:8]=1[CH2:9][CH3:16])[CH2:2][CH3:3]
Reactant: CC1OC(C)OC(C)O1
Reactant: CCCc1[nH]c(C)c(C)c1C(=O)OCC
Product: CCCc1[nH]c(C)c(C)c1CC

Procedure:
2-n-propyl-3-carbethoxy-4,5-dimethyl-pyrrole was reductively alkylated with paraldehyde to yield 2-n-propyl-3-ethyl-4,5-dimethyl-pyrrole. ##STR87##
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][C:9]([OH:12])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:23]([O:12][C:9]([CH3:11])([CH3:10])[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:13])(=[O:25])[CH3:24]
Reactant: CC(C)(O)CNC(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OC(C)(C)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.4 %

Procedure:
2-Hydroxy-2-methylpropylcarbamic acid tert-butylester (510 mg, 2.69 mmol) was dissolved in dichloromethane (7 ml). The solution was cooled to 0° C. Ethyldiisopropylamine (0.70 ml, 4.04 mmol), 4-dimethylaminopyridine (33 mg, 0.27 mmol), and acetic acid anhydride (0.33 ml, 3.50 mmol) were added successively. The reaction mixture was stirred for 16 h, while slowly warming up to room temperature. It was diluted with ethyl acetate (30 ml) and extracted with 1 N hydrochloric acid (30 ml). The aqueous phase was extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (50 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (100 g), using ethyl acetate/heptane (1:2) as eluent, to give 550 mg of 2-(tert-butoxycarbonylamino)-1,1-dimethylethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@@H:14]1[CH2:18][C@@H:17]([C:19](=[O:31])[NH:20][C@:21]3([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][C@H:22]3C=C)[N:16]([C:32](=[O:61])[C@@H:33]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:34][CH2:35][N:36]([CH2:49][CH2:50][CH:51]=[CH2:52])[S:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[N+:46]([O-:48])=[O:47])(=[O:39])=[O:38])[CH2:15]1)=[O:12])[CH2:6]2>C1(C)C=CC=CC=1.ClC1C=CC(OC(C)C)=C(C=1)C=[Ru](Cl)(Cl)C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C>[C:57]([O:56][C:54]([NH:53][C@H:33]1[CH2:34][CH2:35][N:36]([S:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[N+:46]([O-:48])=[O:47])(=[O:38])=[O:39])[CH2:49][CH2:50][CH:51]=[CH:52][C@@H:22]2[CH2:23][C@@:21]2([C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH:20][C:19](=[O:31])[C@@H:17]2[CH2:18][C@@H:14]([O:13][C:11]([N:5]3[CH2:4][C:3]4[C:7](=[CH:8][CH:9]=[CH:10][C:2]=4[F:1])[CH2:6]3)=[O:12])[CH2:15][N:16]2[C:32]1=[O:61])=[O:55])([CH3:60])([CH3:58])[CH3:59]
Reactant: C=CCCN(CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N2Cc3cccc(F)c3C2)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2[Ru](Cl)(Cl)=Cc2cc(Cl)ccc2OC(C)C)c(C)c1
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N3Cc4cccc(F)c4C3)C[C@H]1C(=O)N2
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N3Cc4cccc(F)c4C3)C[C@H]1C(=O)N2
Temperature: 68 °C
Reaction time: 2 h

Procedure:
(3R,5S)-1-((S)-4-(N-(but-3-enyl)-2-nitrophenylsulfonamido)-2-(tert-butoxycarbonylamino)butanoyl)-5-((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)pyrrolidin-3-yl 4-fluoroisoindoline-2-carboxylate (1.65 g, 1.89 mmol) in toluene (400 mL) was degassed by bubbling a stream of nitrogen through the reaction for 1 hr at rt. (5-chloro-2-isopropoxybenzylidene)(1,3-dimesitylimidazolidin-2-yl)ruthenium(V)chloride (0.025 g, 0.038 mmol) was added to the mixture and the mixture was heated to 68° C. (oil bath) and stirred at this temperature for 2 hrs. After removal of solvent, the residue was purified by chromatography (Hexane:Ethyl acetate=1:1) to give (2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-9-(2-nitrophenylsulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa(n)pyrrolo[2,1-c][1,4,9]triazacyclopentadecine-14a-carboxylate as off white solid (1.45 g, 91%). MS: Calcd.: 842; Found: [M+H]+ 843
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:24].[NH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([NH:32]O)=[NH:31])=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]4[O:22][N:32]=[C:30]([C:29]5[CH:34]=[CH:35][C:26]([NH2:25])=[N:27][CH:28]=5)[N:31]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1Cl
Reactant: N=C(NO)c1ccc(N)nc1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4nc(-c5ccc(N)nc5)no4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.6) (178 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (66 mg, 28%). MS (ISP) 471.9 [(M+H)+]; mp 262° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[CH:14]=[N:13][C:12]([C:17]([O:19]C)=O)=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([C:34]([NH:36][C@@H:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C@@H:38]1[NH2:43])=[O:35])=[CH:28]2>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[CH:14]=[N:13][C:12]([C:17]([NH:43][C@@H:38]3[CH2:39][CH2:40][CH2:41][CH2:42][C@@H:37]3[NH:36][C:34]([C:29]3[NH:30][C:31]4[C:27]([CH:28]=3)=[CH:26][C:25]([Cl:24])=[CH:33][CH:32]=4)=[O:35])=[O:19])=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ncc2c(n1)CN(C(=O)OC(C)(C)C)C2
Reactant: N[C@H]1CCCC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1Cc2cnc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)nc2C1

Procedure:
After 6-(tert-Butoxycarbonyl)-5,7-dihydro-2-methoxycarbonylpyrrolo[3,4-d]pyrimidine was hydrolyzed with lithium hydroxide, it was reacted with (±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine hydrochloride in a similar manner to Example 2 to obtain the title compound.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[C:43]([C:50]([F:53])([F:52])[F:51])[CH:42]=1>>[NH2:30][C:29]1[S:28][C:27]([C:44]2[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][C:43]=2[C:50]([F:51])([F:52])[F:53])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: COc1ccc(B(O)O)c(C(F)(F)F)c1
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: COc1ccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC(CN)CC3)c(N)s2)c(C(F)(F)F)c1
Yield: 54 %

Procedure:
Following the procedure for Example 337 starting with tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 4-methoxy-2-(trifluoromethyl)benzeneboronic acid gave 280 as a brown solid (56 mg, 54%). 1H NMR (400 MHz, d4-MeOD) δ 7.65 (d, J=8.6 Hz, 1H), 7.58 (s, 1H), 7.37 (d, J=2.6 Hz, 1H), 7.27 (dd, J=8.6, 2.6 Hz, 1H), 3.94 (s, 3H), 3.72 (s, 3H), 3.19-3.06 (m, 4H), 2.62 (d, J=6.5 Hz, 2H), 1.84 (d, J=12.5 Hz, 2H), 1.57-1.46 (m, 1H), 1.37 (qd, J=11.7, 4.9 Hz, 2H). LCMS (ES+) m/z 510 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH:7]([CH2:12][CH:13]=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][C:5]2=[N:4][O:3]1.B.CO>O1CCCC1>[OH:14][CH2:13][CH2:12][CH:7]1[N:6]2[C:2](=[O:1])[O:3][N:4]=[C:5]2[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=CCC1CCCCc2noc(=O)n21
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: O=c1onc2n1C(CCO)CCCC2
Yield: 70.6 %

Procedure:
To a solution of the product of Example 8 (3.0 g, 0.015 mol) in tetrahydrofuran (20 mL) was added a borane.THF complex (20 mL, 0.020 mol). The reaction stirred for 2 hours upon which methanol (19 mL) was added. The solvent was removed under reduced pressure. The resulting oil was partioned between CH2Cl2 (40 mL) and water (2×20 mL). The organic layer was dried over magnesium sulfate and all solvent was removed under reduced pressure. The residue was chromatographed eluting with 1:1 ethyl acetate/hexane to produce 2.1 g (69%) of the title material.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)=[N:10][N:9]=2)=[CH:4][C:3]=1[N+:21]([O-])=O>CO.O=[Pt]=O>[Cl:20][C:16]1[CH:15]=[C:14]([NH:13][C:11]2[O:12][C:8]([C:5]3[CH:4]=[C:3]([NH2:21])[C:2]([NH2:1])=[CH:7][CH:6]=3)=[N:9][N:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc(-c2nnc(Nc3cccc(Cl)c3)o2)cc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CO
Product: Nc1ccc(-c2nnc(Nc3cccc(Cl)c3)o2)cc1N
Reaction time: 4 h

Procedure:
A suspension of [5-(4-amino-3-nitrophenyl)-[1,3,4]oxadiazol-2-yl]-(3-chlorophenyl)-amine (245 mg, 0.74 mmol) and PtO2 (50 mg) in MeOH (30 mL) was hydrogenated at one atm for 4 h. The catalyst was filtered over Celite and the filtrate was evaporated under reduced pressure to give the title compound. This was used directly in the next reaction.
Reaction SMILES: CO[C:3](=[O:24])[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C@@:6]1([C:11]1[NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[C:18]=2[CH:19]=1)[CH3:10].CS(O)(=O)=O.C([O-])(O)=O.[Na+]>O>[CH3:10][C@@:6]12[C:11]3[NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[C:18]=4[C:19]=3[C:3](=[O:24])[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7]2
Reactant: COC(=O)CN1CCC[C@]1(C)c1cc2c(C(=O)OC)cccc2[nH]1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN1CCC[C@]31C
Temperature: 60 °C
Yield: 44.2 %

Procedure:
In a 25-mL flask, (R)-methyl 2-(1-(2-methoxy-2-oxoethyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (146 mg, 0.44 mmol) was treated with anhydrous MeSO3H (10 mL). The flask was fitted with a reflux condenser and heated to 60° C. for 1 h. Then, the reaction mixture was cooled in an ice-bath and diluted with distilled water (2.0 mL). The pH of the solution was increased to pH-10 by the addition of saturated aq. NaHCO3. The reaction mixture was then extracted with EtOAc (3×20 mL), and the organic extracts were washed with brine (1×20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (20 to 60% EtOAc/hexanes) to give (R)-methyl 11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-7-carboxylate (58 mg 44%). MS (ESI) m/e [M+1]+ 299.0.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[C:20](B(O)O)=[C:21]2[CH2:26][CH2:25][CH2:24][N:22]2[N:23]=1>>[C:7]1([C:5]2[O:6][C:2]([C:20]3[C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=4)=[N:23][N:22]4[CH2:24][CH2:25][CH2:26][C:21]=34)=[CH:3][N:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Reactant: Brc1cnc(-c2ccccc2)o1
Product: c1ccc(-c2ncc(-c3c(-c4ccccn4)nn4c3CCC4)o2)cc1
Yield: 11.7 %

Procedure:
In a similar fashion to Example 1, react 5-bromo-2-phenyloxazole (Combi-Blocks; 120 mg, 0.52 mmol) with 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5; 120 mg, 0.52 mmol) to provide the title compound (20 mg, 12%) as a white solid. MS ESI+ m/e 329 (M+1). 1H NMR (CDCl3) δ 8.78-8.70 (m, 1H), 8.05-7.99 (m, 2H), 7.95-7.89 (m, 1H), 7.82 (s, 1H), 7.81-7.70 (m, 1H), 7.50-7.41 (m, 3H), 7.30-7.25 (m, 1H), 4.31-4.21 (m, 2H), 3.38-3.24 (m, 2H), 2.82-2.66 (m, 2H). HPLC: 97.2%, Rt=16.67 min. TLC (SiO2): Rf0.3 (1:3 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane).
Reaction SMILES: CO[C:3]1([O:10]C)[CH:8]=[CH:7][C:6](=[O:9])[CH:5]=[CH:4]1.[C:12]1([S:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=3)[CH:23]=[C:22]2[C:3]2([OH:10])[CH:4]=[CH:5][C:6](=[O:9])[CH:7]=[CH:8]2)(=[O:19])=[O:20])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC1(OC)C=CC(=O)C=C1
Reactant: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Product: COc1ccc2c(c1)cc(C1(O)C=CC(=O)C=C1)n2S(=O)(=O)c1ccccc1
Yield: 32 %

Procedure:
The title compound was prepared from 4,4-dimethoxy-cyclohexa-2,5-dienone and 1-benzenesulfonyl-5-methoxy-1H-indole, according to Method C, described above. Yield 32%; mp 126-128° C.; 1H NMR (CDCl3) δ 7.73-7.83 (m, 3H), 7.40-7.49 (m, 2H), 7.33-7.40 (m, 2H), 6.76-6.84 (m, 3H), 6.64 (s, 1H), 6.20 (d, J=10 Hz, 2H), 5.40 (s, 1H), 3.67 (s, 3H); 13C NMR (CDCl3) δ 196.6, 185.3, 157.3, 147.9, 141.8, 137.7, 134.3, 133.2, 129.8, 129.7, 129.3, 127.9, 126.9, 116.8, 115.4, 114.4, 104.2, 81.2, 67.9, 55.9; MS (AP+) m/z 396.09 (M++1), 378.08.