Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH3:22])[CH2:3][CH2:4][C:5]1[C:6](=[O:21])[C:7]2[C:12]([C:13](=[O:20])[C:14]=1[CH2:15][CH2:16][C:17](=O)[CH3:18])=[CH:11][CH:10]=[CH:9][CH:8]=2.[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].[ClH:28].Cl>C(O)C>[ClH:28].[ClH:28].[C:23]([NH:26][N:27]=[C:2]([CH3:22])[CH2:3][CH2:4][C:5]1[C:6](=[O:21])[C:7]2[C:12]([C:13](=[O:20])[C:14]=1[CH2:15][CH2:16][C:17](=[N:27][NH:26][C:23](=[NH:24])[NH2:25])[CH3:18])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[NH:25])[NH2:24]
Reactant: CC(=O)CCC1=C(CCC(C)=O)C(=O)c2ccccc2C1=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: CC(CCC1=C(CCC(C)=NNC(=N)N)C(=O)c2ccccc2C1=O)=NNC(=N)N
Yield: 54.1 %

Procedure:
Naphthoquinone (3.12 g, 20 mmol), 4-oxopentanoic acid (13.9 g, 120 mmol) and silver nitrate (2.0 g, 11.8 mmole) are combined in 30% aqueous acetonitrile at 65° C. A solution of ammonium peroxydisulfate (12.0 g, 52.6 mmole) is added dropwise over 30 minutes while the stirred mixture is maintained at 65°-75° C. On cooling, the mixture is extracted with diethyl ether (300 ml). The extract is then washed with water (3×50 ml), 5% NaHCO3 (2×50 ml) and brine (50 ml) and dried over MgSO4. After filtration through active carbon, the ether solution is evaporated to give crude 2,3-bis(3-oxobutyl)-1,4-naphthoquinone which is recrystallized from aqueous ethanol to give 1.45 g product, mp 110°-112° C. This 2,3-bis(3-oxobutyl)-1,4-naphthoquinone (0.456 g, 1.53 mmole), aminoguanidine hydrochloride (0.46 g, 4.3 mmole) and a drop of concentrated HCl are combined in 5 ml of 90% ethanol and heated at reflux for 3 hours. On cooling, 2,3-bis(3-(2-amidinohydrazono)butyl)-1,4-naphthoquinone crystallizes from the reaction mixture, and recrystallization from ethanol gives 400 mg product, mp 181°-183° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:39][C:40]1[CH:41]=[N:42][CH:43]=[C:44](Br)[CH:45]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:39][C:40]1[CH:45]=[C:44]([C:26]2[CH:25]=[CH:24][C:23]([C:20]3([C:17]4[N:13]5[CH2:14][CH2:15][S:16][C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])([CH3:38])[CH2:11][C:12]5=[N:19][N:18]=4)[CH2:22][CH2:21]3)=[CH:28][CH:27]=2)[CH:43]=[N:42][CH:41]=1
Reactant: Brc1cncc(Br)c1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cncc(Br)c5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 3,5-dibromopyridine (947 mg, 4 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (534 mg, 91%) as a brown solid.
Reaction SMILES: [C:1]([N:8]([CH3:34])[C@H:9]([C:31](O)=[O:32])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:35]1([CH:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:42][NH2:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:44]1([CH:41]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:42][NH:43][C:31](=[O:32])[C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:15])[N:8]([C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH3:34])[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: NCC(c1ccccc1)c1ccccc1
Product: CN(C(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCC(c1ccccc1)c1ccccc1

Procedure:
Using Procedure A, Nα-Boc-Nδ-Fmoc-Nα-methylornithine and 2,2-diphenylethylamine afforded a colorless solid: 1H NMR (400 MHz, CDCl3) δ1.39 (s, 10H), 1.57 (m, 2H), 1.77 (m, 1H), 1.98 (m, 1H), 2.50 (s, 3H), 3.19 (m, 2H), 3.80 (m, 1H), 4.00 (m, 1H), 4.19 (t, J=9.5 Hz, 1H), 4.22 (m, 1H), 4.40 (d, J=7.2 Hz, 2H), 4.46 (m, 1H), 7.20-7.34 (m, 12H), 7.41 (t, J=6.6 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H), and 7.79 (d, J=8.5 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[Br:15][C:16]1[N:21]=[C:20]([CH:22]=O)[CH:19]=[CH:18][CH:17]=1.OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[Br:15][C:16]1[N:21]=[C:20]([C:22]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(Br)n3)nc2c1
Temperature: 120 °C
Yield: 47.9 %

Procedure:
To a solution of 2-amino-4,6-dimethoxybenzamide (0.40 g, 2.04 mmol) and 6-bromopyridine-2-carbaldehyde (0.379 g, 2.04 mmol) in N,N-dimethylacetamide (24 mL) was added NaHSO3 (0.544 g, 3.06 mmol) and p-toluenesulfonic acid monohydrate (0.078 g, 0.408 mmol) at rt. The reaction mixture was heated at 120° C. for 6 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with water (10 mL). The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 95:5 dichloromethane/methanol) to give 2-(6-bromopyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.354 g, 48%) as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 11.25 (br s, 1H), 8.36 (d, J=7.81 Hz, 1H), 7.87-8.04 (m, 2H), 6.81 (s, 1H), 6.62 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H); ESI MS m/z 362 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].CN(C=O)C>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Reactant: COC(=O)CBr
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc2oc(C(=O)OC(C)(C)C)c(C)c12
Yield: 92 %

Procedure:
To a round-bottom flask with stir bar was added 4-hydroxy-3-methyl-benzofuran-2 carboxylic acid t-butyl ester (1 mmole), methyl 2-bromoacetate (1.1 eq.) potassium carbonate (5 equiv.) and 10 mL of DMF. The reaction mixture was stirred overnight and then slowly added dropwise to water (10 mL) with stirring. The resulting mixture was extracted with ethyl acetate (2×20 mL), brine (20 mL), dried over magenesium sulfate. Filtration and evaporation of solvent gave 4-methoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a thick oil in 92% yield.
Reaction SMILES: [F:1][C:2]([F:30])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([C@@H:19]([O:21][CH3:22])[CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:23]C2CCCCO2)=[CH:13][C:12]=1[CH2:11][CH2:10]3.C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:30])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([C@@H:19]([O:21][CH3:22])[CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([OH:23])=[CH:13][C:12]=1[CH2:11][CH2:10]3
Reactant: CO[C@H]1C[C@]2(C)C(=C(F)F)CC[C@H]2[C@@H]2CCc3cc(OC4CCCCO4)ccc3[C@H]21
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: CO[C@H]1C[C@]2(C)C(=C(F)F)CC[C@H]2[C@@H]2CCc3cc(O)ccc3[C@H]21
Yield: 93.9 %

Procedure:
A suspension of 1.2 g of 17-difluoromethylene-11β-methoxy-3-tetrahydropyranyloxy-estra-1,3,5(10)-triene in 25 ml of methanol and 2.6 ml of water is refluxed with 1.2 g of oxalic acid for 0.5 hour at a bath temperature of 100° C. Then, it is concentrated by evaporation in a vacuum diluted with ethyl acetate, washed with water, sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/acetone. After crystallization from hexane, 0.9 g of 17-difluoromethylene-11β-methoxy-estra-1,3,5(10)-trien-3-ol is obtained as colorless crystals with a melting point of 245-247° C., [α]D22 +77.3° (c=0.535% in pyridine).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[N:25]1([C:31]([C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:31]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:32])[CH:38]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: O=C(c1cccc(B(O)O)c1)N1CCOCC1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOCc1nc2c(N)nc3cc(-c4cccc(C(=O)N5CCOCC5)c4)cnc3c2n1CC(C)(C)O
Temperature: 110 °C
Yield: 31.3 %

Procedure:
Under a nitrogen atmosphere, a suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.5 g, 3.8 mmol), 3-(morpholine-4-carbonyl)phenylboronic acid (1.07 g, 4.57 mmol), potassium carbonate (1.74 g, 12.6 mmol), dichlorobis(triphenylphosphine)palladium(II)(0.027 g, 0.038 mmol), DME (13 mL), and water (7 mL) was stirred in a pressure vessel. The vessel was sealed, and the suspension was heated at 110° C. for 22 hours and allowed to cool to room temperature. The DME was removed under reduced pressure, and the resulting mixture was extracted with dichloromethane (3×25 mL) and ethyl acetate (25 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting tan solid (2.11 g) was dissolved in dichloromethane (15 mL), purified by automated flash chromatography (40+M silica cartridge, eluting with 5% to 20% methanol in ethyl acetate). The resulting foamy solid was concentrated twice from methyl acetate, and the resulting solid was triturated with acetonitrile, isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to provide 601 mg of 1-{4-amino-2-(ethoxymethyl)-7-[3-(morpholin-4-ylcarbonyl)phenyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol as a white solid, mp 149-152° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)/C=C/C=C/CCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/C=C/CCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
(2E,4E)-Ethyl 7-phenylhepta-2,4-dienoate (355 mg) was dissolved in methanol (5 ml). 2M aqueous sodium hydroxide (1.002 ml) was added and the resulting suspension was heated to 60° C. The reaction mixture was stirred for 2 h. After cooling to room temperature the mixture was acidified with 1M aqueous HCl and extracted three times with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to yield an off-white solid. The residue was taken up with 1M aqueous NaOH (10 ml) and extracted with Et2O. The aqueous layer was acidified with 2M aqueous HCl and extracted twice with EtOAc. The combined EtOAc layer was washed with brine, dried over Na2SO4 and concentrated.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[CH:27]=[CH:26][NH:25][C:5]=2[N:6]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[C:4]2[CH:27]=[CH:26][NH:25][C:5]=2[N:6]=[C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]3)=[CH:14][CH:15]=2)[N:8]=1)=[O:36]
Reactant: CSc1nc(Nc2ccc(N3CCN(C(C)=O)CC3)cc2)nc2[nH]ccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(Nc3nc(S(C)=O)c4cc[nH]c4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
To a solution of 1-(4-(4-(4-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (451 mg, 1.18 mmol) in CH2Cl2 (12 mL), mCPBA (320 mg, 65%, 1.20 mmol) was added. The mixture was stirred at room temperature for 1 h. It was then concentrated in vacuo, the residue was purified by HPLC to give 1-(4-(4-(4-(methylsulfinyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone as a solid (136 mg).
Reaction SMILES: COC(C1SC([I:22])=C(C#N)C=1C1C=CC(C(C)(C)C)=CC=1)=O.[CH2:23]([O:25][C:26]([C:28]1[S:29][C:30](N)=[C:31]([C:47]#[N:48])[C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[S:45][CH3:46])=[CH:35][CH:34]=1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1[S:29][C:30]([I:22])=[C:31]([C:47]#[N:48])[C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[S:45][CH3:46])=[CH:35][CH:34]=1)=[O:27])[CH3:24]
Reactant: COC(=O)c1sc(I)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Reactant: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(-c2ccccc2SC)cc1
Product: CCOC(=O)c1sc(I)c(C#N)c1-c1ccc(-c2ccccc2SC)cc1

Procedure:
Using a method substantially in accordance with the method of 3-(4-tert-butyl-phenyl-4-cyano-5-iodo-thiophene-2-carboxylic acid methyl ester starting with the compound 5-amino-4-cyano-3-(2′methylsulfanyl-biphenyl-4-yl)-thiophene-2-carboxylic acid ethyl ester gives the title compound: 1H NMR (400 MHz, CDCl3) δ 7.53-7.20 (m, 8H), 4.23 (q, 2H, J=7.2 Hz), 2.38 (s, 3H), 1.22 (t, 3H, J=7.0 Hz).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29]>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:21][C:20]=1[C:28]([F:29])([F:30])[F:31]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Product: N#Cc1cc(-c2ccc(Cl)c(C(F)(F)F)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, white solid (63 mg, 65%), MS (ISN) m/z=388.4 [(M−H)+], mp 347° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-chloro-3-trifluoromethyl-phenylboronic acid (72.9 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH2:35][CH:36]4[CH2:38][CH2:37]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.[CH:39]1(N)CCCC1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][NH:34][CH:35]4[CH2:39][CH2:37][CH2:38][CH2:36]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:29])[F:30])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNCC2CC2)CC1
Reactant: NC1CCCC1
Product: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCNC2CCCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[1-[2-(cyclopropylmethyl-amino)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using cyclopentylamine instead of cyclopropylmethylamine. LC-MS: (M+1=543, obsd.=543).
Reaction SMILES: [CH2:1]1[CH2:7][S:4](=[O:6])(=[O:5])[O:3][CH2:2]1.[C:8]([NH2:12])([CH3:11])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1>[C:8]([NH:12][CH2:2][CH2:1][CH2:7][S:4]([OH:3])(=[O:6])=[O:5])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)N
Reactant: O=S1(=O)CCCO1
Solvent: Cc1ccccc1
Product: CC(C)(C)NCCCS(=O)(=O)O

Procedure:
To a solution of 1,3-propanesultone (20 g, 0.164 g) in toluene (100 mL) was added tert-butylamine (90 mL, 62.1 g, 0.85 mol). The mixture was stirred under gentle reflux for 1 hour. The precipitate was filtered, washed with diethyl ether and dried at 20-25° C. Yield 3-(tert-butylamino)propylsulfonic acid 32 g (approximately 100%), as white microcrystals, mp above 280° C., 1H NMR (D2O) δ 1.33 (s, 9H), 2.07 (p, J=7.6 Hz, 2H), 2.99 (t, J=7.6 Hz, 2H), 3.15 (t, J=7.7 Hz, 2H); 13C NMR δ 21.3, 24.3, 39.4, 47.4, 56.5.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH2:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][CH2:30][C:31]1[N:32]=[N:33][N:34]([CH3:36])[N:35]=1)[CH3:22]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:21][CH3:22])[CH2:30][C:31]3[N:32]=[N:33][N:34]([CH3:36])[N:35]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: CCc1ccccc1NCc1nnn(C)n1
Product: CCc1ccccc1N(Cc1nnn(C)n1)[C@H]1c2cc([N+](=O)[O-])ccc2O[C@](C)(C(OC)OC)[C@@H]1O
Yield: 22 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (270 mg, 0.98 mmol) obtained in step 1 of example 2 and N-(2-ethylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:2), to give desired compound (100 mg, yield: 22%).
Reaction SMILES: C([Si](C)(C)O[CH2:7][CH2:8][N:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([CH:18]2[NH:22][CH:21]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH:19]2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=2[F:45])=[O:17])=[CH:11][C:10]1=[O:46])(C)(C)C.Cl.O1CCC[CH2:51]1>>[O:46]=[C:10]1[CH:11]=[C:12]([NH:15][C:16]([CH:18]2[NH:22][CH:21]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[C:20]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH:19]2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=2[F:45])=[O:17])[CH:13]=[CH:14][N:9]1[CH2:8][CH2:7][CH3:51]
Reactant: C1CCOC1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)c(=O)c2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Product: CCCn1ccc(NC(=O)C2NC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-oxo-1,2-dihydro-pyridin-4-yl}-amide (0.1 g, 0.14 mmol) in tetrahydrofuran (3 mL) was added aqueous HCl solution (1N, 3 mL, 3 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and aqueous saturated NaHCO3 solution. The organic layer was separated, washed with water, brine, dried over Na2SO4, then concentrated. The residue was purified by chromatography (10-15% of MeOH in EtOAc) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-oxo-1-propyl-1,2-dihydro-pyridin-4-yl)-amide as a white solid (Yield, 12 mg, 14%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:15]=[C:16]3[CH:22]=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)=[CH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O>[Pd].CO>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[C:16]3[CH:22]=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC=C(c2cnc3[nH]ccc3c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCC(c2cnc3[nH]ccc3c2)CC1
Reaction time: 20 h
Yield: 92.7 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 4-tert-butoxycarbonylamino-cyclohex-1-enyl ester (730 mg, 20 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (490 mg, 20 mmol), Pd(dppf)Cl2 (80 mg) and 2.0M Na2CO3 (3 ml, 6 mmol) in DMF (20 ml) was heated at 80° C. under N2 for 3 hours, and then concentrated. The residue was suspended in water, filtered and the solid was purified by FC to give [4-(1H-Pyrrolo[2,3-b]pyridin-5-yl)-cyclohex-3-enyl]-carbamic acid tert-butyl ester (600 mg) in 96% yield. FIA-MS: m/e=314.05 (M+H). A suspension of the above cyclohexene (300 mg) and 10% Pd/C (200 mg) in a 1:1 mixed solvent of EtOAc and MeOH (30 ml) was shaken under 50 psi H2 for 20 h. Filtration gave [4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-cyclohexyl]-carbamic acid tert-butyl ester (280 mg). FIA-MS: m/e=316.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:13](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:13][O:5][C:4](=[O:6])[C:3]1[C:7]([CH3:12])=[CH:8][C:9]([Cl:11])=[N:10][C:2]=1[Cl:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c(C)cc(Cl)nc1Cl
Yield: 98.4 %

Procedure:
To a solution of 8.05 g (39.1 mmol) of 2,6-dichloro-4-methyl-nicotinic acid [Lamm, G. Ger. Offen. (1977), DE 2538950] in 100 ml of DMF was added 8.10 g (58.6 mmol) of potassium carbonate. While stirring, 12.16 ml=27.7 g (195.4 mmol) of iodomethane was added drop by drop and the reaction mixture was stirred for 6 hours at RT. It was then poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated to give 8.47 g (99%) of the title compound as light yellow solid. MS: 219.0 (M+, 2Cl).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=[O:2].[BrH+][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[OH-].[K+].CN(C)C=O>O>[CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2)=[O:2]
Reactant: N#Cc1ccc(C[BrH+])cc1
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Cn2ccc3cc(C=O)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
Mix 5-formylindole (0.50 g, 3.4 mmol), 4-bromniomethyl-benzonitrile (0.74 g, 3.8 mmol), powdered potassium hydroxide (0.23 g, 4.1 mmol) and dimethylformamide (7 mL) in a flask. Stir at rt overnight. Pour into water (20 mL) and extract with EtOAc/Hexanes (2:1, 3×50 mL). Evaporate solvents to give a yellow oil. Purification on silica using a 10% EtOAc/Hexanes to 30% EtOAc/Hexanes gradient eluent yields the product (0.75 g, 83%). Mass spectrum (ion spray): m/z=259.2 (M−1); 1H NMR (CDCl3) 10.04 (s, 1H), 8.20 (s, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.5 Hz, 1H), 7.22 (d, J=3.1 Hz, 1H), 7.15 (d, J=8.2 Hz, 2H), 6.77 (d, J=3.1 Hz, 1H), 5.44 (s, 2H).