Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)CC.C(O)(=O)CC.[OH:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:29]([CH2:30][CH2:31][C@:13]12[CH3:14])[C@:26]1([CH2:27][OH:28])[C:21](=[CH:22][C:23](=[O:33])[CH2:24][C@@H:25]1[CH3:32])[CH2:20][CH2:19]3.C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:29]([CH2:30][CH2:31][C@:13]12[CH3:14])[C@:26]1([CH2:27][OH:28])[C:21](=[CH:22][C:23](=[O:33])[CH2:24][C@@H:25]1[CH3:32])[CH2:20][CH2:19]3
Reactant: C[C@H]1CC(=O)C=C2CC[C@H]3[C@@H]4CC[C@@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(=O)O
Solvent: CO
Product: C[C@H]1CC(=O)C=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO

Procedure:
A solution of 17α,19-dihydroxy-1α-methyl-4-androsten-3-one dipropionate in methanol is refluxed for about two hours with aqueous sodium carbonate. The solvent is removed and the residue dissolved in chloroform. The chloroform extract is washed well with water, dried over magnesium sulfate and evaporated under vacuum. The residue which remains is crystallized from acetonitrile to yield 17β,19-dihydroxy-1α-methyl-4-androsten-3-one.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][NH:14][CH2:15][C@H:16]([C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1)[OH:17]>ClCCl>[CH3:13][N:14]1[CH2:15][C@H:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[O:17][C:1]1=[O:2]
Reactant: CNC[C@@H](O)c1cnccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CN1C[C@H](c2cnccn2)OC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
The optical purity is upgraded as follows: Carbonyldiimidazole (4.26 g, 1.1 equiv., 26.2 mmol) is dissolved in dichloromethane (80 mL). To this solution is slowly added, via cannula addition, (1R)-2-(methylamino)-1-pyrazin-2-ylethanol (3.66 g, 23.9 mmol) dissolved in dichloromethane (60 mL). The reaction is stirred at room temperature for 16 h. The solvent in vacuo and purification is accomplished by silica gel column chromatography (98:2 dichloromethane-methanol, sample and silica gel loaded in dichloromethane). Any uncyclized carbamate collected off the column is dissolved in methanol, to which is added a catalytic amount of 1 M NaOH and the solution is refluxed until completely cyclized. This freshly cyclized material is then purified by column chromatography as above. The combined pure oxazolidinone fractions are then concentrated in vacuo producing an 88% yield of (5R)-3-methyl-5-pyrazin-2-yl-1,3-oxazolidin-2-one (3.77 g, 21.0 mmol) as a white solid. This material is upgraded by chiral preparative HPLC to give material with >95% ee. MP: 113.5-114.1°; 1H NMR (400 MHz, CDCl3) δ 8.84, 8.62, 8.58, 5.62, 4.02, 3.80, 2.94; 13C NMR (100 MHz, CDCl3) δ 157.4, 153.2, 144.8, 144.1, 142.7, 72.2, 51.6, 31.1. MS (CI) m/z (rel. intensity) 180 (MH+, 12), 197 (45), 180 (12), 138 (35), 137 (17), 136 (99), 122 (11), 107 (24), 96 (14), 95 (10), 58 (11); HRMS (FAB) Found 180.0781; Specific Rotation [α]D25 +20 (c 0.95, methylene chloride); Anal. Found: C, 53.38; H, 5.03; N, 23.35.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:27]=[CH:26][C:25]2[C:11]3[NH:12][C:13](=[O:24])[C:14]4[N:15]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=4)[C:10]=3[CH2:9][C:8]=2[CH:7]=1>CN(C)C=O>[CH3:1][NH:2][C:3](=[O:4])[NH:5][C:6]1[CH:27]=[CH:26][C:25]2[C:11]3[NH:12][C:13](=[O:24])[C:14]4[N:15]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=4)[C:10]=3[CH2:9][C:8]=2[CH:7]=1
Reactant: CN=C=O
Reactant: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1ccc(N)cc1C3
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1ccc(NC(=O)NC)cc1C3
Reaction time: 12 h

Procedure:
0.44 ml of methyl isocyanate is added dropwise with stirring to a suspension of 580 mg of ethyl 8-amino-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate in 10 ml of dimethylformamide and stirring is continued for 12 hours at a temperature close to 20° C. The reaction mixture is then filtered, rinsed with dimethylformamide and dried at 35° C. under vacuum (1 mm Hg; 0.13 kPa). 320 mg of ethyl 8-(3-methylureido)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate are obtained as a dihydrate in the form of a beige solid melting above 260° C. (analysis % calculated C: 53.59, H: 5.25, N: 17.36; % found C: 53.2, H: 4.7, N: 17.7).
Reaction SMILES: O/[C:2](/[CH3:12])=[CH:3]\[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=O.[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14].N1CCCCC1>CCO>[CH3:12][C:2]1[CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[NH:18][C:16](=[O:17])[C:15]=1[C:13]#[N:14]
Reactant: C/C(O)=C/C(=O)c1ccncc1
Reactant: N#CCC(N)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(-c2ccncc2)[nH]c(=O)c1C#N
Temperature: 25 °C
Yield: 11.6 %

Procedure:
To a solution of (2Z)-3-hydroxy-1-(4-pyridinyl)-2-buten-1-one (8 g, crude, 49 mmol) and cyanoacetamide (4.12 g, 49 mmol) in anhydrous EtOH (100 mL) was added piperidine (4.17 g, 49 mmol) under N2 at 75° C. The mixture was heated at reflux for 1 h, and then cooled to room temperature. After filtration, the solid was collected and washed with H2O to give the crude product (4 g) as two isomers. After separation by HPLC, 1.8 g of 6-methyl-2-oxo-1,2-dihydro-4,4′-bipyridine-3-carbonitrile and 1.2 g of 4-methyl-6-oxo-1,6-dihydro-2,4′-bipyridine-5-carbonitrile were obtained. The identity of 6-methyl-2-oxo-1,2-dihydro-4,4′-bipyridine-3-carbonitrile was established by nOE analysis. 1H NMR (400 MHz, DMSO-d6) δ 12.79 (br. s., 1H), 8.75 (d, 2H), 7.58 (d, 2H), 6.37 (s, 1H), 2.31 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[CH:12]([N:15]=[C:16]=[O:17])([CH3:14])[CH3:13].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][O:1][C:16](=[O:17])[NH:15][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:7]=1
Reactant: CC(C)N=C=O
Reactant: O=C(CO)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)NC(=O)OCC(=O)c1ccc(Cl)cc1
Yield: 49.1 %

Procedure:
A mixture of 2-hydroxy-1-(4-chloro-phenyl)-ethanone (4.7914 g, 28 mmol), prepared in the previous step, isopropyl isocyanate (4.1 ml, 42 mmol) and triethylamine (2.83 ml, 28 mmol) in 100 ml of benzene was refluxed under nitrogen for approximately 24 hours. The solid formed was collected by filtration and dried under high vacuum to give 3.5184 g (49%) of isopropyl-carbamic acid 2-(4-chloro-phenyl)-2-oxo-ethyl ester as an off-white solid. Recrystallization of a portion of this solid from isopropyl alcohol gave an analytically pure sample, mp 163-164° C.
Reaction SMILES: [N:1]([C@@H:4]([CH:6]([CH3:8])[CH3:7])[CH3:5])=[C:2]=[O:3].Cl.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][NH:29][CH2:30]4)=[CH:25][CH:24]=3)[N:20]=[C:19]([NH2:33])[N:18]=2)[CH2:13][CH2:12]1>>[NH2:33][C:19]1[N:20]=[C:21]([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][N:29]([C:2]([NH:1][C@H:4]([CH3:5])[CH:6]([CH3:8])[CH3:7])=[O:3])[CH2:30]3)=[CH:25][CH:24]=2)[CH:22]=[C:17]([N:14]2[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]2)[N:18]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: CC(C)[C@@H](C)N=C=O
Agent: Cl
Product: CC(C)[C@@H](C)NC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 5 starting from (2R)-2-isocyanato-3-methylbutane (Alfa Aesar, Cat. #L20241) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=438.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O-:16])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[C:17]1([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[NH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:25]1([C:23](=[N:24][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:5]([CH3:8])([CH3:6])[CH3:4])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C([O-])N1CCOC(c2ccc(Br)cc2)C1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)C1
Temperature: 90 °C
Reaction time: 18 h
Yield: 148.3 %

Procedure:
2-(4-bromophenyl)morpholine-4-carboxylate (47 g), diphenylmethanimine (29.9 g), BINAP (6.41 g) and Pd2(dba)3 (3.14 g) were dissolved under Argon in dry and de-aerated toluene (940 ml) and treated with sodium tert-butoxide (18.5 g). The dark brown mixture was stirred at 90° C. for 18 h. The yellow/brown reaction mixture was diluted with toluene (700 ml), cooled to room temperature and extracted twice with water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The crude product was diluted with 300 ml hexane, stirred for 1 h and filtered off, leading to an orange solid (68 g) which was purified by column chromatography (silicagel, 20% ethylacetate/heptane). The combined and concentrated fractions were suspended in hexane, stirred for 17 h, filtered off and dried in vacuo to yield (S)-tert-butyl 2-(4-(diphenylmethyleneamino)phenyl)morpholine-4-carboxylate (54.1 g, 89%) as a yellow solid. MS (ISP): 443.3 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[O:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:23]2([OH:26])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)=[CH:6][CH:7]=1
Reactant: O=C1CCOCC1
Reactant: Brc1ccc(I)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)nc2)CCOCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-bromo-5-iodopyridine (2.00 g) in tetrahydrofuran (20 mL) and diethyl ether (10 mL) was added dropwise 1.6M n-butyllithium hexane solution (4.40 mL) at −78° C. The mixture was stirred at −78° C. for 30 min under argon atmosphere, and a solution of tetrahydro-4H-pyran-4-one (0.651 mL) in tetrahydrofuran (10 mL) was added dropwise thereto at −78° C. The reaction mixture was slowly warmed to −50° C., aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.932 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.Cl>[OH:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]([C:12]([F:11])([F:21])[F:20])[O:1]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: O=Cc1ccc(O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2ccc(O)cc2OC1C(F)(F)F
Temperature: 60 °C
Yield: 31.6 %

Procedure:
A mixture of 2,4-dihydroxy benzaldehyde (20.0 g, 0.145 mole) and ethyl 4,4,4-trifluorocrotonate (36.58 g, 0.217 mole) was dissolved in anhydrous DMF (40 mL). The solution was warmed to 60° C., treated with anhydrous K2CO3 (40.0 g, 0.290 mole), and maintained at 80° C. for 48 h. The reaction was cooled to room temperature, diluted with 3N HCl, and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford an oil. The oil was passed through the silica plug and the plug was washed with 20% EtOAc in hexane to give yellow solid (13.22 g, 31.6%): LCMS m/z 311.05 (M+Na). 1H NMR (CDCl3/400 MHz) 7.67 (s, 1H), 7.09 (d, 1H, J=8.8 Hz), 6.46 (m, 2H), 5.67 (q, 1H, J=6 Hz), 4.29 (q, 2H, J=7.2 Hz), 1.33 (t, 3H, J=7.2 Hz).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:12])[CH3:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Br:13]Br>O1CCOCC1>[Br:13][CH2:11][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: CC(=O)c1ccc2c(c1)CCO2
Reactant: BrBr
Solvent: C1COCCO1
Product: O=C(CBr)c1ccc2c(c1)CCO2
Reaction time: 0.25 h
Yield: 38 %

Procedure:
To a stirred solution of 1-(2,3-dihydro-benzofuran-5-yl)-ethanone (2.5 g, 15.4 mmol) (Lancaster) in dioxane (2 mL) was added dropwise a solution of bromine (2.96 g, 18.5 mmol) in dioxane (60 mL). After stirring 15 minute the mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel (2:1 hexane-dichloromethane) to provide 1.41 g (38%) of 2-bromo-1-(2,3-dihydro-benzofuran-5-yl)-ethanone.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.[SH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([S:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[O:10][CH3:11]
Reactant: CCOC(=O)CCCS
Reactant: COc1cc(Br)c(C=O)cc1OC
Product: CCOC(=O)CCCSc1cc(OC)c(OC)cc1C=O
Yield: 27 %

Procedure:
Ethyl 4-(3,4-dimethoxy-6-formylphenylthio)butyrate was synthesized from 6-bromoveratraldehyde and ethyl 4-mercaptobutyrate in the same manner as Example 2. After vacuum concentration of an extracted solution, the residue was crystallized from isopropyl ether to yield ethyl 4-(3,4-dimethoxy-6-formylphenylthio)butyrate (Yield 27%) as slightly yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][CH:18]([C:22](=O)[CH3:23])[C:19](=O)[CH3:20])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][NH2:26]>CO.ClCCl>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][C:18]2[C:22]([CH3:23])=[N:25][NH:26][C:19]=2[CH3:20])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(=O)C(Cc1cn(C(=O)OC(C)(C)C)c2ncccc12)C(C)=O
Solvent: ClCCl
Solvent: CO
Product: Cc1n[nH]c(C)c1Cc1cn(C(=O)OC(C)(C)C)c2ncccc12
Reaction time: 2 h

Procedure:
To 3-(2-acetyl-3-oxo-butyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (513, 1.20 g, 3.63 mmol) in methanol (15.0 mL), cooled to −20° C. under an atmosphere of nitrogen, was added hydrazine (0.128 g, 4.00 mmol) in dichloromethane (6.0 mL). The reaction was stirred for 2 hours. The reaction was concentrated to remove the solvents, and the residue was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 60% ethyl acetate in hexane to give a white solid (514, 1.0 g, 84.4%). MS (ESI) [M+H+]+=327.4.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+].[OH-].[K+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:5][CH2:4][N:3]=1
Reactant: CC1=NCCc2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: CC1=NCCc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A solution of (±) 1-methyl-3,4-dihydroisoquinoline (2.57 g, 17.7 mmol) in conc. sulfuric acid (10 ml) was added dropwise to a stirred mixture of potassium nitrate (1.93 g, 19.1 mmol) in conc. sulfuric acid (10 ml) at −5° C. The mixture was allowed to reach room temperature over 2 h and then heated at 60° C. for 4 h. The reaction mixture was poured into ice-water (100 ml) and basified (pH 9) with KOH pellets. Extraction into dichloromethane (3×50 ml), drying over anhydrous sodium sulfate and evaporation in vacuo yielded the crude product. Purification by chromatography through silica gel, eluting with (0.5% 0.88 NH3: 4.5% CH3OH: 95% CH2Cl2) afforded the title compound as a dark brown oil (1.92 g, 57%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[F:20])[C:9]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:26][O-:27].[Na+].Cl>C1COCC1.CO>[F:20][C:13]1[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=1[C:10]1[C:9]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:27][CH3:26])[N:11]=1
Reactant: C[O-]
Reactant: COC(=O)c1cc(OCC(C)C)c(-c2cc(OC)ccc2F)nc1Cl
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(OCC(C)C)c(-c2cc(OC)ccc2F)nc1OC
Temperature: 60 °C
Reaction time: 48 h

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 2-chloro-6-(2-fluoro-5-methoxyphenyl)-5-isobutoxynicotinate (248 mg) in THF (5.0 mL) was added a 28% solution of sodium methoxide in methanol (3.42 mL). The reaction mixture was stirred at room temperature for 1 hr and further at 60° C. for 48 hr. 6N Hydrochloric acid (0.44 mL) was added to the reaction mixture, and the resulting sodium chloride was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was heated with conc. sulfuric acid (108 μL) and methanol (10 mL) under reflux for 3 hr. The reaction mixture was neutralized with sodium hydrogen carbonate, and the solvent in the reaction mixture was evaporated under reduced pressure and the residue was filtered. The solvent in the filtrate was evaporated under reduced pressure to give a crude product of the title compound (213 mg) as a yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)[CH:15]=1)[N:6]=[C:5]2[NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:34]=[CH:33]2.Br[CH2:47][CH2:48][O:49][CH3:50].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5]([NH:29][C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:34]=[CH:33]4)=[N:6][C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=4)[CH:15]=3)=[N:8]2)=[CH:3][C:2]=1[O:1][CH2:47][CH2:48][O:49][CH3:50]
Reactant: COCCBr
Reactant: COc1cc2nc(-c3cccc(NC(=O)c4cccnc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(NC(=O)c4cccnc4)c3)nc2cc1OC
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 5-(6-hydroxy-7-methoxy-2-(3-(nicotinamido)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.108 g, 0.179 mmol), 1-bromo-2-methoxyethane (0.054 g, 0.389 mmol) and K2CO3 (0.052 g, 0.449 mmol) in DMF (2 mL) were heated at 85° C. for 3 h. The mixture was allowed to cool to RT and the volatiles were removed in vacuo. The residue was purified by preparative tic (SiO2, CH2Cl2/MeOH 9:1) to give tert-butyl 5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-(nicotinamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. The material was taken directly on to the next step. HPLC retention time 5.802 mins.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:33]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:34])=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: O=C(c1cn(C(=O)N2CCCCC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (the preparation of which have been described in example 69) with commercially available piperidine-1-carbonyl chloride as electrophile, the title compound was obtained as a white powder.
Reaction SMILES: C([O:3][C:4]([C@@H:6]([NH:15][C@H:16]1[CH2:22][S:21][CH2:20][C@@H:19]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[N:18]([CH2:28][C:29]([OH:31])=[O:30])[C:17]1=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C.[OH-].[Na+]>>[C:4]([C@@H:6]([NH:15][C@H:16]1[CH2:22][S:21][CH2:20][C@@H:19]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[N:18]([CH2:28][C:29]([OH:31])=[O:30])[C:17]1=[O:32])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC[C@@H](c2cccs2)N(CC(=O)O)C1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCc2ccccc2)C(=O)O)CSC[C@H]1c1cccs1
Yield: 76.7 %

Procedure:
90 mg of α-{6(R)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-3(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl}acetic acid (prepared as described in Example 17 above) were hydrolyzed with aqueous sodium hydroxide in the manner described in Example 5, to give 65 mg of the title compound as a powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:18]([CH3:20])[CH3:19])[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])=[O:12])=[CH:6][CH:5]=1)[CH3:2].S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl.C(OCC)(=O)C.CCCCCC>[Cl:23][C:5]1[CH:6]=[C:7]([CH:10]([CH:18]([CH3:19])[CH3:20])[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])=[O:12])[CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CC#CCOC(=O)C(c1ccc(OCC)cc1)C(C)C
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC#CCOC(=O)C(c1ccc(OCC)c(Cl)c1)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
Into a solution of 0.15 g (0.55 mM) of Compound No. 2 (2-butynyl 2-(4-ethoxyphenyl)isovalerate) in 5 ml of chloroform, 0.76 g (5.5 mM) of thionyl chloride was added, and the mixture was stirred for 16 hours at room temperature. After condensing the reaction mixture, the condensate was subjected to silica gel column chromatography while using a 1:30 mixture of ethyl acetate and n-hexane as an eluent, thereby 0.14 g of the colourless and only compound No. 24 was obtained (yield: 80%).
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:54]1[N:59]=[C:58]([CH3:60])[CH:57]=[CH:56][N:55]=1.[N:61]1([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:60][C:58]1[CH:57]=[CH:56][N:55]=[C:54]([N:64]2[CH2:63][CH2:62][N:61]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:66][CH2:65]2)[N:59]=1
Reactant: Cc1ccnc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccnc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
Palladium acetate (45 mg, 0.2 mmol), BINAP (62 mg, 0.1 mmol) and cesium carbonate (650 mg, 2 mmol) were suspended in anhydrous 1,4-dioxane (3 ml) under an argon atmosphere and sonicated for 45 minutes. 2-Bromo-4-methylpyrimidine (173 mg, 1 mmol) and tert-butyl piperazine-1-carboxylate (208 mg, 1.3 mmol) were dissolved in 3 ml anhydrous 1,4-dioxane and the resulting solution was added to the catalyst-containing mixture. The resulting mixture was stirred at 110° C. overnight, afterwards diluted with ethyl acetate and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by column chromatography (silica, gradient from DCM to DCM/ethyl acetate 8/2) to yield 120 mg of a brown oil (0.43 mmol, 43%) MS (APCI) m/z=279.2 [M+1]+.