Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:55][O:56][CH3:57])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([S:46][CH2:47][C:48]([O:50]C(C)(C)C)=[O:49])=[C:35]3[C:39]([O:41]C(C)(C)C)=[O:40])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:55][O:56][CH3:57])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([S:46][CH2:47][C:48]([OH:50])=[O:49])=[C:35]3[C:39]([OH:41])=[O:40])=[O:28])[N:25]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(SCC(=O)OC(C)(C)C)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(SCC(=O)O)SCC12)c1csc(N)n1
Reaction time: 2 h
Yield: 46.3 %

Procedure:
A solution of 200 mg of the product of Step B in 4 ml of 66% aqueous formic acid was stirred for two hours and a half at 50° C. The cooled solution was filtered and evaporated. The residue was re-dissolved in a mixture of methanol and acetonitrile which was evaporated and the treatment was repeated. The residue was again dissolved in 5 ml of methanol and after carbon black was added, the mixture was stirred for a further 2 hours, then filtered. 30 ml of ether were added dropwise with stirring for hour and the white precipitate was separated and dried at 50° C. to obtain 53 mg of racemic 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-(carboxymethylthio)-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid melting at 190° to 200° C. (with decomposition)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[CH:17]1([CH2:20][N:21]([CH2:34][CH2:35][CH3:36])[CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=2[O:32][CH3:33])[CH2:19][CH2:18]1.Cl>ClCCl.CO>[ClH:1].[CH:17]1([CH2:20][N:21]([CH2:34][CH2:35][CH3:36])[CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:14](=[O:16])[C:13]#[C:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[Cl:1])=[CH:27][C:26]=2[O:32][CH3:33])[CH2:19][CH2:18]1
Reactant: CCCN(CCOc1ccc(N)cc1OC)CC1CC1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCN(CCOc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1OC)CC1CC1

Procedure:
Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid and 185 mg (0.66 mmol) of 4-[2-(cyclopropylmethylpropylamino)ethoxy]-3-methoxyphenylamine. Yield: 180 mg (59% of theory); melting point: 185° C.-188° C.; C26H28ClF3N2O3 (M=508.96)*HCl; calc.: molecular ion peak (M+H)+: 509/511 (Cl); found: molecular ion peak (M+H)+: 509/511 (Cl); Rf value: 0.35 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [CH2:1]([OH:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[Li].[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(O)C>C1COCC1>[CH2:1]([O:7][CH2:9]/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[CH3:14])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6]
Reactant: C/C=C/C=C/CO
Reactant: CCCCCC
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCO
Product: C/C=C/C=C/COC/C=C/C=C/C

Procedure:
A mixture of 10 g of the polymer from Example 17, 2.2 ml of sorbyl alcohol (2,4-hexadienol) and 0.1 g of lithium metal in 100 ml of THF was refluxed under nitrogen for 18 hours. The mixture was then cooled and a 10-ml portion was poured into 100 ml of hexane containing 2 ml of ethanol to obtain the solid product. To further purify, it was redissolved in 10 ml of THF and suction filtered through a fine frit into 100 ml of water. The precipitated solid was collected and dried.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][C:27](Br)=[C:20]3[C:21]=2[C:16](=[CH:17][CH:18]=[CH:19]3)[C:15]1=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCN2C(=NCCC2)CC1>O>[CH2:6]([O:13][N:14]1[C:15](=[O:29])[C:16]2[CH:17]=[CH:18][C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:20]3[C:21]=2[C:22](=[CH:25][CH:26]=[CH:27]3)[C:23]1=[O:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1c2cccc3c(Br)ccc(c23)C(=O)N1OCc1ccccc1
Reactant: C1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: O=C1c2cccc3c(N4CCCC4)ccc(c23)C(=O)N1OCc1ccccc1

Procedure:
Pyrrolidine (3 mL) was added to 2-benzyloxy-6-bromo-benzo[de]isoquinoline-1,3-dione (0.8 g, 2.1 mmol, from Example M) in the presence of DBU (0.05 mL). The mixture was refluxed for 2 hours and poured into water (50 mL). The precipitate formed was filtered and dried to give 0.8 g of 2-benzyloxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione. The hydrogenation of 2-benzyloxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.4 g, 1.1 mmol) in the presence of 10% Pd/C (0.2 g) in DMA (30 mL) gave 0.27 g of the title compound, mp 268-270° C.;
Reaction SMILES: [Br:1][C:2]1[N:3]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[N:31]=[N:32][N:33](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:34]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([CH2:11][N:12]1[C:16]([CH2:17][OH:18])=[C:15]([Cl:19])[N:14]=[C:13]1[CH2:20][CH2:21][CH2:22][CH3:23])[CH:7]=[CH:6]2.Cl>ClCCl.C(O)C>[Br:1][C:2]1[N:3]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[NH:34][N:33]=[N:32][N:31]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([CH2:11][N:12]1[C:16]([CH2:17][OH:18])=[C:15]([Cl:19])[N:14]=[C:13]1[CH2:20][CH2:21][CH2:22][CH3:23])[CH:7]=[CH:6]2
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nn(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c(Br)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nn(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To 1-{[3-bromo-2-[2-(2-(triphenylmethyl)-2H-tetrazol-5-yl)phenyl]-2H-indazol-5-yl]methyl}-2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazole (obtained in Example 13) in dichloromethane (8.4 ml ) was dropwise added 14.7% hydrogen chloride in ethanol (5.6 ml), and the mixture was stirred at room temperature for 17 hours. The mixture was concentrated in an evaporator, and thereto were added water (5 ml), 10N aqueous sodium hydroxide (1.25 ml), and 1N aqueous sodium hydroxide (5 ml), followed by filtration. The cake was washed twice with water (5 ml), and conc. hydrochloric acid was dropwise added to the filtrate while stirring so as to adjust its pH to 4-5. The resultant solid was filtered off, washed twice with ion-exchanged water (2 ml), and dried in vacuo at 37° C. to give 11 mg of 1-{[3-bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-2H-indazol- 5-yl]methyl}-2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazole.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26](O)=[O:27])([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])[CH3:2].[CH:31]([NH2:34])([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26](=[O:27])[NH:34][CH:31]([CH3:33])[CH3:32])([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:29])([CH3:30])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)O)c1)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)NC(C)C)c1)N2
Yield: 94.1 %

Procedure:
2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (820 mg, 2 mmol), isopropylamine (0.5 mL, 6 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1140 mg, 3 mmol) in dichloromethane (10 mL) and triethyl-amine (0.84 mL, 6 mmol) was stirred at 25° C. for 5 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[3-(1-isopropylcarbamoyl-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.85 g, 94%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C27H37N3O3 (M+H)+: 452.61, observed: 452.2.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:24])[NH:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([OH:14])=O)[N:3]=[CH:2]1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH3:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[C:39]1([O:43][CH2:44][CH2:45][CH3:46])[CH2:42][NH:41][CH2:40]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[OH-].[Na+]>CN(C=O)C>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH:8][C:9]([NH:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([N:41]2[CH2:40][C:39]([CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH:33]3[CH3:32])([O:43][CH2:44][CH2:45][CH3:46])[CH2:42]2)=[O:14])=[O:24])[N:3]=[CH:2]1
Reactant: CCCOC1(C2CCCCC2C)CNC1
Reactant: COc1ccc(CC(NC(=O)NCCc2c[nH]cn2)C(=O)O)cc1
Agent: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCOC1(C2CCCCC2C)CN(C(=O)C(Cc2ccc(OC)cc2)NC(=O)NCCc2c[nH]cn2)C1
Reaction time: 3 h
Yield: 17.8 %

Procedure:
To 97 mg (0.29 mmol) of 2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)-propanoic acid (cf. preparation 2-3) dissolved in 2 mL of DMF are added 94 mg (0.29 mmol) of 3-(2-methylcyclohexyl)-3-propoxyazetidine trifluoroacetate, 70 mg (0.37 mmol) of EDC and 45 mg (0.33 mmol) of HOBt. After 3 hours, the reaction medium is hydrolysed with aqueous 1N sodium hydroxide solution and then extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and concentrated. The crude product obtained is purified by preparative HPLC. 33 mg of 1-[2-(1H-imidazol-4-yl)ethyl]-3-{1-(4-methoxybenzyl)-2-[3-(2-methylcyclohexyl)-3-propoxyazetidin-1-yl]-2-oxoethyl}urea trifluoroacetate are obtained in a yield of 18%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-])=O)[C:9]=1[Cl:10])[C:5]#[N:6].[Cl-].[NH4+]>C1COCC1.CO.O.[Fe]>[NH2:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([Br:1])[C:9]=1[Cl:10])[C:5]#[N:6]
Reactant: N#Cc1cc(Br)c(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(N)c(Cl)c(Br)c1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
(I1D): A mixture of 3-bromo-4-chloro-5-nitrobenzonitrile (0.99 g, 3.79 mmol), iron (1.057 g, 18.93 mmol) and ammonium chloride (2.025 g, 37.9 mmol) in THF, MeOH and water (60 ml, 1:1:1) was heated to reflux for 1 h. More iron (0.5 g) and NH4Cl (2 g) added, heated for another 2 h and then cooled to RT. Filtered off solid, the filtrate was concentrated to remove the organic solvent. The residue was diluted with water, extracted with EtOAc twice, dried and concentrated to dryness. The resulting solid was trituard with EtOAc, solid was filtered off through celite pad and the filtrate was concentrated to give 0.88 g of 3-amino-5-bromo-4-chlorobenzonitrile as yellow solid which was used as such in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]2)=[CH:11][CH:10]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:34][CH2:35][N:36]([CH2:39][C:40]([NH2:42])=[O:41])[CH2:37][CH:38]=2)=[CH:29][C:28]=1[O:43][CH3:44].C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:44][O:43][C:28]1[CH:29]=[C:30]([C:33]2[CH2:38][CH2:37][N:36]([CH2:39][C:40]([NH2:42])=[O:41])[CH2:35][CH:34]=2)[CH:31]=[CH:32][C:27]=1[NH:26][C:15]1[N:14]=[CH:13][C:12]2=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:17]2[N:16]=1
Reactant: COc1cc(C2=CCN(CC(N)=O)CC2)ccc1N
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1cc(C2=CCN(CC(N)=O)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Into an 8-dram vial was added Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (210.0 mg, 0.5625 mmol), 2-[4-(4-Amino-3-methoxy-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetamide (180 mg, 0.69 mmol), N,N-Diisopropylethylamine (0.2940 mL, 1.688 mmol) and 1-Methoxy-2-propanol (2 mL, 20 mmol). The reaction mixture was heated at 100° C. overnight. After 18 h, the product, 2-(4-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-3,6-dihydro-2H-pyridin-1-yl)-acetamide, was isolated after purification with reverse phase prep-hplc (gilson) as a brown solid (46 mg, 17%). LCMS (E/I+) 582 (M+H). NMR 1H (DMSO-d6)-10.04 (br s, 1H), 8.97 (s, 1H), 8.15 (d, 1H, J=8.43 Hz), 7.96 (s, 1H), 7.80 (d, 1H, J=7.44 Hz), 7.72 (s, 2H), 7.48 (m, 1H), 7.23 (d, 1H, J=8.4 Hz), 7.13 (m, 2H0, 7.0-6.93 (m, 3H), 6.17 (s, 1H0, 4.01-3.2 (series of s, m along with the water peak, 12H), 2.78 (m, 2H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[C:14]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:13]=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1.C(OCC)(=O)C>[S:18]1[CH:19]=[CH:20][N:21]=[C:17]1[NH:16][C:14]1[N:15]=[C:10]([CH2:9][OH:8])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Nc2nccs2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cccc(Nc2nccs2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.48 g of 6-(((tert-butyl(dimethyl)silyl)oxy)methyl)-N-thiazol-2-ylpyridin-2-amine was dissolved in 100 ml of tetrahydrofuran. Under cooling with ice, a tetrabutylammonium fluoride-tetrahydrofuran solution (1.0 M, 20.2 ml) was added followed by stirring at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and then washed with phosphate buffer (pH 6.8). The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([CH:15]=[O:16])=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O[CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1.CS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:6]2[C:5]([CH:15]([O:16][CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][CH2:7]2)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN1CCC(O)CC1
Reactant: Cc1c(-c2ccccc2)nc(C=O)n1CCc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccccc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1

Procedure:
To a solution of 5-methyl-1-phenethyl-4-phenyl-imidazole-2-carbaldehyde (example 103B) (50 mg, 0.172 mmole) in CHCl3 (1 mL) is added 4-hydroxy-N-methylpiperidine (198 mg, 1.72 mmoles). Methanesulfonic acid is added dropwise until a purple colour developed. The reaction is completed (TLC control). A saturated solution of Na2CO3 is added to reach pH 10. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by preparative TLC over silica gel using (CH2Cl2:MeOH:NH4OH) (92.5:7.5:0.75) to give 1-methyl-4-(1-methyl-piperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]2)[C:5]2[C:6](C3C=NC=C(Cl)C=3)=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=1.[F-].[K+].CS(C)=O.CCN(C(C)C)C(C)C>C(OCC)(=O)C>[CH3:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([CH2:20][N:19]2[C:5]3[CH:6]=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=3[N:3]=[CH:2]2)[CH2:22][CH2:23]1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H]1CC[C@H](Cn2cnc3cc(C#N)ncc32)CC1
Temperature: 100 °C

Procedure:
To a vial were added ((2S,4R)-4-methoxypyrrolidin-2-yl)methanol, HCl (0.303 g, 1.81 mmol), 2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1) (0.805 g, 1.810 mmol), potassium fluoride (0.210 g, 3.62 mmol), DMSO (4 ml) and DIEA (0.948 ml, 5.43 mmol). The reaction vial was capped and heated to 100° C. for 8 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 4-(5-chloropyridin-3-yl)-2-(2S,4R)-2-(hydroxymethyl)-4-methoxypyrrolidin-1-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C26H31ClN6O2 [M+H]+ 495. found 495.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([CH3:12])=[C:10]([C:13]([OH:15])=O)[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([CH:24]=1)[C:22]#[N:23].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:10]2[CH:9]=[N:8][N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:11]=2[CH3:12])=[O:15])[CH:18]=[CH:19][C:20]=1[O:25][CH2:26][C:27]([CH3:29])([CH3:28])[CH3:30])#[N:23]
Reactant: Cc1c(C(=O)O)cnn1C1CCCCC1
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)cnn1C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
1-Cyclohexyl-5-methylpyrazole-4-carboxylic acid (1.2 g), 5-amino-2-neopentyloxybenzonitrile (1.1 g), triethylamine (1.7 g) and diethyl cyanophosphate (1.4 g) were added to dimethylformamide (15 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Methanol was added to the residue to allow crystallization. The crystals were recrystallized from hydrous dimethylformamide to give the title compound (1.2 g), melting point: 126–128° C.
Reaction SMILES: [C@@H:1]12[C:9](=[O:10])[NH:8][C:7](=[O:11])[C@@H:2]1[CH2:3][CH:4]=[CH:5][CH2:6]2>[Pd].C(O)C>[C@@H:2]12[C:7](=[O:11])[NH:8][C:9](=[O:10])[C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3]2
Reactant: O=C1NC(=O)[C@@H]2CC=CC[C@H]12
Agent: [Pd]
Solvent: CCO
Product: O=C1NC(=O)[C@@H]2CCCC[C@H]12
Yield: 96 %

Procedure:
Cis-4-cyclohexene-1,2-dicarboximide (10.9 g) was hydrogenated over 10% palladium on carbon (1 g) in absolute ethanol (420 ml) at 50 psi for 10 minutes. The mixture was filtered then evaporated to give cis-cyclohexane-1,2-dicarboximide (10.6 g). To anhydrous diethyl ether (200 ml) was cannulated under nitrogen a 1M diethyl ether solution (200 ml) of lithium aluminium hydride. To the foregoing solution, under reflux, was added cis-cyclohexane-1,2-dicarboximide (10.6 g) portionwise over 10 minutes. The reaction mixture was heated to reflux for 3 hours. After cooling to 0° C., water (7 ml) was added followed by 4N sodium hydroxide (7.6 ml) and water (23 ml). The white suspension was stirred whilst warming to room temperature. The solid was removed by filtration then the filtrate dried (sodium sulphate) and evaporated to give a cream oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([CH3:23])([CH3:22])[C:4]=2[N:5](C(OCC)=O)[N:6]=1.[Li+].[OH-]>CO.CCOC(C)=O>[NH2:1][C:2]1[C:3]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([CH3:23])([CH3:22])[C:4]=2[NH:5][N:6]=1
Reactant: CCOC(=O)n1nc(N)c2c1C(C)(C)N(C(=O)OC(C)(C)C)C2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1Cc2c(N)n[nH]c2C1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a slurry of 5-tert-butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (25.00 g, 77.1 mmol) in MeOH (50 mL) was added LiOH (1.92 g, 77.1 mmol). The reaction was stirred at room temperature for 2 h then concentrated. The crude reaction mixture was taken up in EtOAc (50 mL) then washed with NaHCO3 (20 mL) and water (20 mL). The organic layer was dried (MgSO4), filtered and concentrated to give an orange solid which was triturated with ACN then filtered and rinsed with ACN (50 mL) to give the title compound B1(i) as a white solid (14.8 g, 76%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.40-1.46 (m, 9H), 1.47-1.54 (m, 6H), 4.03-4.17 (m, 2H), 4.95 (br. s., 1H), 11.15 (s, 1H). Mass spectrum: Calcd for C12H21N4O2 (M+H): 253. Found 253.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([CH3:17])([CH3:16])[C:13](O)=[O:14])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[N:18]1(C(N)=O)[CH2:22]CC[CH2:19]1>>[CH3:19][N:18]([CH3:22])[C:13](=[O:14])[C:12]([C:9]1[CH:10]=[CH:11][C:6]([C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:7][CH:8]=1)([CH3:17])[CH3:16]
Reactant: NC(=O)N1CCCC1
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)C2CC2)cc1
Product: CN(C)C(=O)C(C)(C)c1ccc(C(=O)C2CC2)cc1

Procedure:
2-(4-Cyclopropanecarbonyl-phenyl)-2-methyl-proprionic acid, pyrrolidineamide;
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:46][CH3:47])=[C:13]([NH:16][C:17]3[N:30]4[C:21](=[N:22][C:23]5[C:28]([C:29]4=[O:31])=[C:27]([F:32])[CH:26]=[CH:25][CH:24]=5)[C:20]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:19]=4[N:18]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5].[CH3:49][NH2:50]>C1COCC1>[CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:46][CH3:47])=[C:13]([NH:16][C:17]3[N:30]=[C:21]([NH:22][C:23]4[CH:24]=[CH:25][CH:26]=[C:27]([F:32])[C:28]=4[C:29]([NH:50][CH3:49])=[O:31])[C:20]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=5)(=[O:38])=[O:37])[C:19]=4[N:18]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4cccc(F)c4c(=O)n13)N(C(=O)CN(C)C)CCC2
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCCN3C(=O)CN(C)C)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (5.0 g, 7.47 mmol) in THF (200 ml) was added 2.0 M methylamine in THF (74.7 ml, 149 mmol) and the resulting reaction was stirred overnight at rt. The crude reaction was adsorbed to silica gel and purified by LC (DCM to 5% MeOH/DCM) to give 2-({2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (3.2 g, 61%). ESIMS (M+H)+=701.
Reaction SMILES: [S:1]([C:5]1[S:13][C:8]2=[CH:9]N=C[CH:12]=[C:7]2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].S1C2C=C[N:19]=[CH:18]C=2C=C1.S1C2=CN=CC=C2C=C1>>[S:1]([C:5]1[S:13][C:8]2[CH:9]=[CH:18][N:19]=[CH:12][C:7]=2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: NS(=O)(=O)c1cc2ccncc2s1
Reactant: c1cc2sccc2cn1
Agent: c1cc2ccsc2cn1
Product: NS(=O)(=O)c1cc2cnccc2s1

Procedure:
The title compound was prepared according to the procedure described for 2-sulfamoylthieno[2,3-c]pyridine (Example 1) except thieno[3,2-c]pyridine was substituted for thieno[2,3-c]pyridine. This title compound was obtained in 41% yield; m.p. 193°-194° C., after crystallization from ethyl acetate.