Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH3:6][S:7]([C:10]#[N:11])(=[O:9])=[O:8]>ClCCl>[CH3:6][S:7]([C:10]1[CH:5]2[CH2:1][CH:2]([CH:3]=[CH:4]2)[N:11]=1)(=[O:9])=[O:8]
Reactant: C1=CCC=C1
Reactant: CS(=O)(=O)C#N
Solvent: ClCCl
Product: CS(=O)(=O)C1=NC2C=CC1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.93 g of cyclopentadiene (120 mmol) was added to a solution of 10.51 g of methanesulfonyl cyanide (100 mmol) in 30 ml of dichloromethane within 5 minutes at -20° C. The colorless solution was stirred for another 2 hours at room temperature and then the solvent was distilled off, and the Diels-Alder adduct remains as yellowish solid. Properties of the compound were:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:18]=[C:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=[C:15]([OH:26])[C:8]=2[S:9][C:10]=1[NH:11]C(=O)C)=[O:5])[CH3:2].OS(O)(=O)=O>CO>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:18]=[C:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=[C:15]([OH:26])[C:8]=2[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(NC(C)=O)sc2c(O)cc(Cc3ccccc3)cc12
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCOC(=O)c1c(N)sc2c(O)cc(Cc3ccccc3)cc12
Reaction time: 72 h

Procedure:
Compound 01-6 (2.1 g, 5.7 mmol) was dissolved in MeOH (250 mL), H2SO4 (1 mL) was added and the mixture was stirred for 3 days. Another batch of 01-6 (450 mg, 1.2 mmol) was added and the mixture was stirred further for 14 days while monitoring the reaction each third day by HPLC. After completion the mixture was concentrated to half of the original volume. Water was added and the pH was cautiously adjusted to 8 with conc. NH4OH. The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (100 mL), brine (100 mL) and dried over Na2SO4. The solvent was removed in vacuo to give product a-1 (2.05 g, 6.3 mmol, 91%) as a greenish brown foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[N+:11]([CH3:14])([O-:13])=[O:12].C([O-])(=O)C.[NH4+].O>C(O)(=O)C>[F:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[CH:14][N+:11]([O-:13])=[O:12])=[CH:3][C:2]=1[F:1]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(F)c(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])C=Cc1ccc(F)c(F)c1

Procedure:
A solution of 3,4-difluorobenzaldehyde (5.05 g), nitromethane (5.3 mL) and ammonium acetate (6.3 g) in glacial acetic acid (60 mL) is heated at 110° C. for 16 hours, allowed to cool and poured into water (300 mL). The solution is extracted with EtOAc (2×200 mL). The combined extract is washed with 10% NaHCO3, water and dried over sodium sulfate, filtered and evaporated in vacuo to afford 1,2-difluoro-4-(2-nitro-vinyl)benzene (4.2 g). MS: 198 (M+H); 1H NMR (300 MHz, CDCl3) □7.9 (1H, d, J=10 Hz); 7.5 (1H, d, 10 Hz); 7.3 (2H, m); 6.95-7.15 (1H, m).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=2)[CH2:24][CH2:25]1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCN(c3ccccn3)CC2)cc1
Yield: 152.3 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (1.0 g), 1-(2-pyridyl)piperazine (1.4 g) and potassium carbonate (4.2 g) in dimethylformamide (20 ml) was stirred at 60-70° C. for 2.5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown oil. The obtained brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) to give a pale-yellow oil (2.5 g). The obtained pale-yellow oil was crystallized from ethyl acetate and the crystals were recrystallized from ethyl acetate to give the title compound (1.4 g) as white crystals, m.p.=100-101° C.
Reaction SMILES: [CH3:1][Li].[CH2:3]([CH:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][N:11]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O>CCOCC>[CH2:3]([CH:10]1[C:15]([OH:16])([CH3:1])[CH2:14][CH2:13][CH2:12][N:11]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCN1CCCC(=O)C1CCCCCCC
Reactant: [Li]C
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCN1CCCC(C)(O)C1CCCCCCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
Methyl lithium (7 ml, 2 M solution in ether) was injected, under nitrogen, into a stirred solution of 2-n-heptyl-1-n-octylpiperidin-3-one (3.4 g) in dry ether (100 ml) at -78°. The mixture was allowed to warm gradually to room temperature. After 3 hours, thin layer chromatography indicated that some starting material remained. The solution was cooled to -78° and methyl lithium (3 ml, 2 M solution in ether) was injected. The mixture was allowed to warm gradually to room temperature and was allowed to stand for 2 days. Water (10 ml) was added dropwise and the ether phase was separated, dried over magnesium sulphate and evaporated in vacuo. The product was purified by column chromatography to give 2-n-heptyl-3-hydroxy-3-methyl-1-n-octylpiperidine as a yellow gum (1.47 g, 41% yield).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].Br[CH2:34][CH2:35][CH2:36][OH:37].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:34][CH2:35][CH2:36][OH:37])[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: OCCCBr
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCO)C[C@H]1Cc1c[nH]c2ccccc12
Reaction time: 9 h
Yield: 77.3 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (5 g) and 3-bromopropanol (1.68 g) in N,N-dimethylformamide (40 ml) was heated at 60° C. in the presence of potassium carbonate (4.55 g). After 9 hours, the reaction mixture was poured into water (400 ml) and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the obtained residue was purified by column chromatography on silica gel using dichloromethanemethanol (30:1) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(3-hydroxypropyl)-2-(1H-indol-3-ylmethyl)piperazine (4.36 g) as a powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:28][C:27](=[O:29])[CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][Mg+].[Br-]>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH:25]3[CH2:28][C:27]([CH3:30])([OH:29])[CH2:26]3)[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)C1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(O)CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)C1
Temperature: -78 °C

Procedure:
3-[1-(3-Benzyloxy-phenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanone (100 mg, 248 mols) was dissolved in dry THF (1.0 mL) under inert atmosphere and cooled to −78° C. A solution of MeMgBr (40 μL, 322 mols) in toluene: THF (75:25) was added slowly to the cooled solution. After 24 h of reaction at rt the reaction was cooled to 0° C. and quenched with NH4Cl sat. aq. solution and the aqueous layer was washed with EtOAc (2×). The organic layers where combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified by silica gel column chromatography [Jones Flashmaster, 10 g/70 mL cartridge, eluting with 2-5% ((7N NH3) in MeOH):CH2Cl2], yielding 3-[1-(3-Benzyloxy-phenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]-1-methyl-cyclobutanol as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N-]>>[CH2:23]([O:22][C:20]([CH:19]1[CH:15]2[CH:14]1[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16]2)=[O:21])[CH3:24]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)N1CC=CCC1
Product: CCOC(=O)C1C2CCN(C(=O)OCc3ccccc3)CC21

Procedure:
Alternatively, 1-benzyloxycarbonyl-1,2,5,6-tetrahydropyridine can be subjected to reaction with ethyl diazoacetate under rhodium acetate catalysis, to provide ethyl-3-benzyloxycarbonyl-3-azabicyclo[4.1.0]heptane-7-carboxylate. Ester hydrolysis with sodium hydroxide then provides the corresponding carboxylic acid, which can be converted as described in Section VIII to give amino or substituted amino derivatives.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[C:29]1([C:35]2[N:39]3[CH2:40][CH2:41][NH:42][CH2:43][C:38]3=[C:37]([C:44]([NH:46][CH:47]3[C:52]([CH3:54])([CH3:53])[CH:51]4[CH2:55][C:48]3([CH3:56])[CH2:49][CH2:50]4)=[O:45])[N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH:1]1([C:4]([N:42]2[CH2:41][CH2:40][N:39]3[C:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:36][C:37]([C:44]([NH:46][CH:47]4[C:52]([CH3:53])([CH3:54])[CH:51]5[CH2:55][C:48]4([CH3:56])[CH2:49][CH2:50]5)=[O:45])=[C:38]3[CH2:43]2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: CC12CCC(C1)C(C)(C)C2NC(=O)c1nc(-c2ccccc2)n2c1CNCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC12CCC(C1)C(C)(C)C2NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)C1CC1)CC2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of cyclopropanecarboxylic acid (1.2 eq.) in anhydrous DMF (2 mL) was distributed EDCI (1.6 eq.), HOBt (1.3 eq.) and TEA (5 eq.). The vial was sealed and stirred for 40 minutes at room temperature. Compound 39 (1 eq. in 1 mL of anhydrous DMF) was added to the vial which was then sealed and stirred overnight at room temperature. The solvent was removed by centrifugal evaporation under reduced pressure. The residue was dissolved in DCM (2 mL), and washed sequentially with 10% K2CO3 solution (1 mL) and water (1 mL). The water wash was then re-extracted with DCM (0.5 mL), the combined organic extracts were evaporated to dryness under reduced pressure. The desired product, Compound 119, was isolated by mass directed LC. LCMS (+ESI) m/z 447.38 [M+H]+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:45])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:42]=3)=[C:18]([O:43][CH3:44])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:35])([F:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:45])=[CH:17][C:18]=4[O:43][CH3:44])=[N:42][C:27]2=3)[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To the solution 0.17 g (0.27 mmole) of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-71) in 10 mL of dichloromethane was added 5 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 1 hour. After removal of the solvents under reduced pressure. Then dichloromethane and saturated sodium carbonate were added. The mixture was extracted with dichloromethane three times. The combined organic layers were washed three times with sodium carbonate, three times with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Dichloromethane and ether were added to the residue, followed by hexane to give a precipitate. The solid was collected by filtration, washing with hexane to give 0.125 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-piperidin-4-yl-benzamide (I-72) as a white solid.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1.[OH:15][CH2:16]/[C:17](=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[OH:15][CH2:16][C@@H:17]([C@H:25]([S:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1)[CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19]
Reactant: CC(C)(C)OC(=O)/C(=C/CCCCc1ccccc1)CO
Reactant: COc1ccc(S)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(S[C@H](CCCCc2ccccc2)[C@H](CO)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A solution of n-butyl lithium in hexanes (0.6 mL, 1.4 mmol) is added slowly to a mixture of 4-methoxybenzenethiol (2 g, 14 mmol) in THF (10 mL) at 0° C. After 2 minutes a solution of t-butyl (E)-2-hydroxymethyl-7-phenylhept-2-enoate (2.2 g, 7.59 mmol) in THF (7 mL) is added and the reaction is allowed to warm to room temperature. After 1 hours the reaction is concentrated in vacuo and the crude product is purified by column chromatography using gradient elution (silica, 15 to 30% ether in petroleum ether) to give (±)-t-butyl (2R*,3R*)-2-hydroxymethyl-3-(4-methoxyphenylsulfanyl)-7-phenylheptanoate (3 g, 92%): 1H NMR (300 MHz, CDCl3) δ 7.39-7.34 (m, 2H), 7.30-7.25 (m, 2H), 7.20-7.13 (m, 3H), 6.86-6.81 (m, 2H), 4.07-3.98 (m,1H), 3.93-3.86 (m, 1H), 3.80 (s, 3H), 3.26-3.19 (m, 1H), 2.67-2.60 (m, 1H), 2.58 (t, J=7.2 Hz, 2H), 2.38 (t, J=6.6 Hz, 1H), 1.65-1.47 (m, 6H), 1.46 (s, 9H); MS (FAB) m/e 430 (M+).
Reaction SMILES: CCCCC.[H-].[Na+].[CH3:8][N:9]([CH3:28])[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=2)[C:13]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:12][N:11]=1.[CH:29]([N:32]=[C:33]=[O:34])([CH3:31])[CH3:30]>C1COCC1>[CH3:28][N:9]([CH3:8])[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=2)[C:13]([S:24]([NH:27][C:33]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:34])(=[O:25])=[O:26])=[CH:12][N:11]=1
Reactant: Cc1cccc(Nc2nc(N(C)C)ncc2S(N)(=O)=O)c1
Reactant: CC(C)N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1cccc(Nc2nc(N(C)C)ncc2S(=O)(=O)NC(=O)NC(C)C)c1
Yield: 97.1 %

Procedure:
Pentane washed sodium hydride (22.0 mmol, 2.05 eq) was suspended in THF (100 mL) and 2-(dimethylamino)-4-[(3-methylphenyl)amino]-5-pyrimidinesulfonamide (3.72 g, 10.74 mmol) was added as a powder over a 30 minute period. After 90 minutes the solidified reaction was loosened by adding more THF (30 mL) followed by adding isopropyl isocyanate (1.09 mL, 11.06 mmole, 2.05 eq). After stirring 90 minutes a small portion of isopropyl isocyanate (150 mL) was added to complete the reaction. The THF was removed under reduced pressure and the residue was dissolved in warm water (100 mL). The pH was adjusted to 4 with acetic acid and the aqueous phase was extracted with four 150 mL portions of ethyl acetate. The organic portions were combined, dried (Na2SO4), decanted and the solvent removed to yield pale yellow crystals (4.11 g, 10.43 mmol, 97%). The crude material was crystallized once from ethanol/water to yield 3.45 g (8.76 mmol, 81%) of pure product, m.p. 178.5°-179° C.
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[CH2:11]([C:13]1[NH:17][CH:16]=[C:15]([C:18]#[N:19])[CH:14]=1)[CH3:12].C([O-])(=O)C.[Na+]>ClCCCl>[CH2:11]([C:13]1[NH:17][C:16]([CH:9]=[O:10])=[C:15]([C:18]#[N:19])[CH:14]=1)[CH3:12]
Reactant: CCc1cc(C#N)c[nH]1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1cc(C#N)c(C=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
POCl3 (3.3 ml, 35.67 mmol) was added to 1,2-dichloroethane (4 ml), then anhydrous DMF (2.75 ml, 35.67 mmol) was added very slowly. The mixture was stirred at room temperature for ˜10 minutes. 5-Ethyl-1H-pyrrole-3-carbonitrile (Intermediate 30, 856 mg, 7.13 mmol) in 1,2-dichloroethane (2 ml) was added dropwise and the mixture was heated at 80° C. for ˜30 minutes. The mixture was cooled to room temperature and sodium acetate (2.5 g/5 ml) was added and the mixture was stirred for 1 h. The brown/black emulsion was extracted with DCM (4×50 ml). The combined organic phase was washed with water (2×50 ml) dried over Na2SO4 and concentrated in vacuo to give the title compound. (819 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[C:13](O)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:17][CH:16]=4)[C:13]([NH:35][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NC1CCCCC1
Reactant: O=C1C=C(O)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1
Product: O=C1C=C(NC2CCCCC2)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-4-hydroxy-5-(4-morpholinophenyl)-1H-pyrrol-2(5H)-one (0.124 g, 0.3 mmol) and cyclohexylamine (0.48 ml, 4.2 mmol) according to method 7 described above.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C@H:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C@@H:19]([NH:26][C:27](=[O:28])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)[CH3:18])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: C[C@H](N=C=O)c1ccccc1
Product: C[C@H](NC(=O)Oc1ccc2c(c1)CCN2Cc1ccccc1)c1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (35.0 mg, 0.155 mmol) using the same procedure employed for Example 2 (2), but with (S)-α-methylbenzylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (14.8 mg, 27%) having the following characteristics.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16]OS(C)(=O)=O)=[CH:12][C:11]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=3)=[N:10]2)=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)=[CH:12][C:11]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=3)=[N:10]2)=[CH:30][CH:31]=1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)ccc1F
Reactant: CN1CCNCC1
Product: Cc1cc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)ccc1F
Yield: 71.8 %

Procedure:
Following the procedure of Example 1(10), 2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 71.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: ClCCOc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCOc1ccncc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 5.7 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (300 mg, 0.94 mmol), (prepared as described for the starting material in Example 15), 4-(2-chloroethoxy)pyridine hydrochloride (155 mg, 0.79 mmol) and potassium carbonate (260 mg, 1.9 mmol) in NMP (20 ml) was heated at 90° C. for 2 hours, allowed to cool to ambient temperature and stirred for a further 18 hours. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 95/5) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline (20 mg, 7%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]2[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH:7]=1>C(O)(C(F)(F)F)=O.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:16]=[C:17]([F:21])[CH:18]=[CH:19][CH:20]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2C2CC(=O)NC(c3cccc(F)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cc(Br)ccc2OC2CCNCC2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(F)c2)N1
Yield: 70.1 %

Procedure:
A solution of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-phenyl]-6-chloro-2′-(3-fluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.35 g, 0.5 mmol) in TFA (2 mL) and dichloromethane (2 mL) was stirred at r.t. for 0.5 h. The solution was diluted with DCM, washed with 1N Na2CO3 aq. (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, concentrated to give title compound as a yellow solid (Yield: 0.21 g, 70%).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][N:18](C(OCC3C=CC=CC=3)=O)[CH2:17][CH2:16]2)(=O)=O)=CC=1.[O:31]1[CH2:35][CH2:34][C@@H:33](O)[CH2:32]1>>[O:31]1[CH2:35][CH2:34][C@@H:33]([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[CH2:32]1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: O[C@@H]1CCOC1
Product: C1CC(OCCO[C@@H]2CCOC2)CCN1
Yield: 78.5 %

Procedure:
Using benzyl 4-(2-{[(4-methylphenyl)sulfony]oxy}ethoxy)piperidine-1-carboxylate (4.00 g, 9.23 mmol) produced in Reference Example 1 (1c) and (3R)-tetrahydrofuran-3-ol (1.05 g, 12.0 mmol), the desired title compound (1.56 g, yield 79%) was obtained by the same method as in Reference Examples 1 (1d) and 1 (1e).