Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[C:8]2[CH:16]=[C:15]([CH:17]=O)[S:14][C:9]=2[N:10]([CH2:12][CH3:13])[CH:11]=1)=[O:5])[CH3:2].Cl.[NH2:21][OH:22].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[C:8]2[CH:16]=[C:15]([CH:17]=[N:21][OH:22])[S:14][C:9]=2[N:10]([CH2:12][CH3:13])[CH:11]=1)=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)c1cn(CC)c2sc(C=O)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2sc(C=NO)cc2c1=O
Yield: 80 %

Procedure:
In 50 ml of warm ethanol was dissolved 0.5 g of 4,7-dihydro-7-ethyl-2-formyl-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester. The solution was cooled to room-temperature, then 0.2 g of hydroxylamine hydrochloride was added followed by 2 ml of a 5%-solution of sodium hydroxide. After filtration, 4,7-dihydro-7-ethyl-2-hydroxyiminomethyl-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester was obtained in a yield of 80%.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C@H:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:16][C:17]1[C:20](=[O:21])[C:19](=O)[C:18]=1[NH:23][C:24]1[C:25]([OH:35])=[C:26]([CH:32]=[CH:33][CH:34]=1)[C:27]([N:29]([CH3:31])[CH3:30])=[O:28])C>CO>[OH:35][C:25]1[C:24]([NH:23][C:18]2[C:17](=[O:16])[C:20](=[O:21])[C:19]=2[NH:13][C@@H:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8]2([CH3:12])[CH2:9][O:10][CH2:11]2)=[CH:34][CH:33]=[CH:32][C:26]=1[C:27]([N:29]([CH3:31])[CH3:30])=[O:28]
Reactant: CCOc1c(Nc2cccc(C(=O)N(C)C)c2O)c(=O)c1=O
Reactant: Cc1ccc([C@H](N)C2(C)COC2)o1
Solvent: CO
Product: Cc1ccc([C@H](Nc2c(Nc3cccc(C(=O)N(C)C)c3O)c(=O)c2=O)C2(C)COC2)o1
Temperature: 50 °C
Yield: 59 %

Procedure:
471 mg (2.6 mmol, 1.3 eq) of C—(R)-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine were added to 609 mg (2.0 mmol, 1 eq) of 3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N,N-dimethylbenzamide dissolved under hot conditions in 40 ml of methanol. The reaction medium was heated at 50° C. for 17 hours. The methanol was evaporated off and the residue (green oil) was chromatographed on silica gel (column puriFlash IR-50SI-80G, Spot II) eluted with dichloromethane/methanol (97/3). The amorphous solid was taken up with diethyl ether to give a yellow powder which was recrystallized from n-propanol. 519 mg of 2-hydroxy-N,N-dimethyl-3-(2-{[(R)-(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}-3,4-dioxocyclobut-1-enylamino)benzamide were obtained. Yield=70%.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]1=2.[CH3:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]#[N:27]>>[CH3:20][N:21]1[C:25]([C:6]2[CH:5]=[CH:4][C:3]3[C:2](=[O:1])[CH2:11][CH2:10][CH2:9][C:8]=3[CH:7]=2)=[CH:24][CH:23]=[C:22]1[C:26]#[N:27]
Reactant: Cn1cccc1C#N
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)CCCC2=O

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 1-methyl-2-cyanopyrrole according to the coupling procedure as described in example 1. MS (ES) m/z 251.2; HRMS: calcd for C16H14N2O+H+, 251.11789; found (ESI, [M+H]+), 251.1186.
Reaction SMILES: [C:1]1([CH:7]([OH:35])[CH2:8][CH2:9][C:10]2[NH:11][C:12]([CH3:34])=[C:13]([C:30]([O:32][CH3:33])=[O:31])[CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)[C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:36](O)=[O:37]>O>[CH:36]([O:35][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][C:10]1[NH:11][C:12]([CH3:34])=[C:13]([C:30]([O:32][CH3:33])=[O:31])[CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:37]
Reactant: CCOC(=O)C1=C(CCC(O)c2ccccc2)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Reactant: O=CO
Solvent: O
Product: CCOC(=O)C1=C(CCC(OC=O)c2ccccc2)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of diastereoisomers of 2-(3-phenyl-3-hydroxypropyl)-3-carboethoxy-5-carbomethoxy -4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (100 mg) in formic acid (2 ml) is stirred for 24 hours at room temperature, then it is diluted with water (10 ml) and extracted with ethyl ether (15 ml); the organic phase is washed with a NaHCO solution (5%, 3×5 ml , water (3×5 ml), dried (Na2SO4) and concentrated under vacuum to give 2-(3-formyloxy-3-phenylpropyl)-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine, diastereoisomer mixture identical to the compound obtained in example 1.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]([C:19]2[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)[N:9]=1)=[O:7].Cl.O>CO>[CH3:4][O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]([C:19]2[N:20]=[N:21][C:22]([O:2][CH3:1])=[CH:23][CH:24]=2)[N:9]=1)=[O:7]
Reactant: C[O-]
Reactant: COC(=O)c1cc(-c2ccccn2)n(-c2ccc(Cl)nn2)n1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(-c2ccccn2)n(-c2ccc(OC)nn2)n1
Reaction time: 19 h

Procedure:
Sodium methoxide (1.530 g) was added to the above-obtained 1-(6-chloro-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid methyl ester (2.981 g) in methanol (190 mL) at room temperature, followed by stirring for 19 hours. Aqueous 1N hydrochloric acid (19 mL) was added to the reaction mixture. Water was added to the residue obtained by evaporation of methanol under reduced pressure. The insoluble product was recovered by filtration, and dried, to thereby give 1-(6-methoxy-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid methyl ester as a solid (2.571 g, 87%).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:26])=[CH:12][C:13]([CH:15]([CH3:25])[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][C:4]=2[O:3]1.[ClH:28].[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])[CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:28].[CH3:27][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:26][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][N:32]3[CH2:31][CH2:30][O:29][CH2:34][CH2:33]3)=[CH:12][C:13]([CH:15]([CH3:25])[CH2:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][C:4]=2[O:3]1
Reactant: CC(CCCc1ccccc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Reactant: O=C(O)CCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CC(CCCc1ccccc1)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
1.25 g. (3.5 mmoles) of 4,4-dimethyl-9-hydroxy-7-(4-phenyl-1-methylbutyl)-1,2,3,4-tetrahydrocyclopenta[c] [1] benzopyran, 0.76 g. (3.63 mmoles) of γ-morpholinobutyric acid hydrochloride and 0.76 g. (3.70 mmoles) of dicyclohexylcarbodiimide are combined in 75 ml. of methylene chloride and stirred at room temperature for 24 hours. The insoluble by-product of dicyclohexylurea is removed by filtration and the methylene chloride solution is concentrated to 20 ml. Cyclohexane is added until the desired compound is obtained as a colorless solid. Recrystallization from methylene chloride/cyclohexane gives the desired crystalline product.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:7](=[O:23])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:30][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:10]=[CH:9][N:8]3[C:13]([C:12]=2[CH3:14])=[C:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:7]3=[O:23])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(CO)cc3)ccn2c1=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(CBr)cc3)ccn2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
327 mg of ethyl 1-cyclopropyl-8-(4-hydroxymethylphenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (Example 51) was dissolved in 11 ml of dichloromethane. 380 mg of carbon tetrabromide was added to the obtained solution, and they were cooled to 0° C. 355 mg of triphenylphosphine was added to the reaction mixture, and they were stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by the silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to obtain 291 mg of ethyl 8-(4-bromomethylphenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[K+].O.[F:6][CH:7]([F:34])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[C:12]([C:30]([O:32][CH3:33])=[O:31])[CH:11]=1>CC(O)=O>[C:2]([N:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH:7]([F:34])[F:6])=[CH:11][C:12]=1[C:30]([O:32][CH3:33])=[O:31])[CH:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:21][CH2:22]1)(=[O:3])[NH2:1]
Reactant: COC(=O)c1cc(OCC(F)F)ccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [N-]=C=O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(OCC(F)F)ccc1N(C(N)=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 12 h
Yield: 95 %

Procedure:
1.95 g of potassium isocyanate in solution of 4 ml of water are added to a solution of 6.63 g of 1,1-dimethylethyl 4-{[4-(2,2-difluoroethoxy)-2-(methoxycarbonyl)phenyl]amino}piperidine-1-carboxylate obtained in stage 3.3 in 40 ml of AcOH. The mixture is stirred at AT for 12 h 00. It is extracted with AcOEt and the extract is washed with a saturated K2CO3 solution and then with water. It is dried over MgSO4, filtered and evaporated under reduced pressure to give 6.95 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[SH:10].Br[CH:12]([CH2:17][CH2:18][CH2:19][Br:20])[C:13](OC)=[O:14].O>CN(C)C=O>[Br:20][CH2:19][CH2:18][CH2:17][CH:12]1[C:13](=[O:14])[NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=2[S:10]1
Reactant: COC(=O)C(Br)CCCBr
Reactant: Cc1cc(N)c(S)cc1C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc1C)SC(CCCBr)C(=O)N2
Yield: 69.3 %

Procedure:
To a solution of 3.06 g of 2-amino-4,5-dimethylthiophenol in 50 ml of dimethylformamide was added 5.48 g of methyl 2,5-dibromovalerate at room temperature with stirring. The mixture was stirred for 14 hours, poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was washed with a mixture of ether and hexane to obtain 4.35 g (69.3%) of 2-(3-bromopropyl)-6,7-dimethyl-2H-1,4-benzothiazin-3(4H)-one as crystals. Recrystallization from methanol gave prisms, m.p. 151°-153° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([CH2:20][CH3:21])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[CH:17][CH:16]=[CH:15][C:14]=3[Br:19])C.[BH4-].[Li+]>O1CCCC1>[Br:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11]1[C:6]([CH2:5][CH2:4][OH:3])([CH2:20][CH3:21])[O:7][CH2:8][CH2:9][C:10]2=1
Reactant: CCOC(=O)CC1(CC)OCCc2c1[nH]c1c(Br)cccc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1(CCO)OCCc2c1[nH]c1c(Br)cccc21
Yield: 75.1 %

Procedure:
To a solution of (8-bromo-1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester (1.03 g, 2.8 mmol) in tetrahydrofuran at room temperature was added 2.0 M solution of lithium borohydride in tetrahydrofuran. The mixture was heated to reflux for 5 hours. It was quenched with 5% HCl solution, followed by saturated sodium bicarbonate. It was extracted with ethyl acetate, extracts were dried over magnesium sulfate, and it was evaporated to dryness. Crystallization with diethyl ether afforded 0.682 g (75%) of the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 8.01 (br, 1H), 7.45 (d, 1H), 7.32 (d, 1H), 7.00 (t, 1H), 4.07 (m, 1H), 3.99 (m, 1H), 3.72 (m, 1H), 3.67 (m, 1H), 2.87 (m, 1H), 2.75 (dt, 1H), 2.68 (dd, 1H), 2.24 (m, 1H), 2.08 (m, 1H), 2.02 (m, 1H), 1.93 (m, 1H), 0.94 (t, 3H); ESI (+) MS m/e=324 (MH+), ESI (−) MS m/e=322 (MH−).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:5])#[N:2].[CH2:12]=O>C1N2CCN(CC2)C1.C1(C)C=CC=CC=1>[C:1]([C:3](=[CH2:12])[C:4]([O:6][CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:5])#[N:2]
Reactant: C=O
Reactant: CC(C)(C)COC(=O)CC#N
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: C=C(C#N)C(=O)OCC(C)(C)C

Procedure:
46.5 (0.3 mole) of neopentyl α-cyanoacetate, 8.1 g (0.27 mole) of paraformaldehyde, 140 g of toluene and 46.5 mg of triethylenediamine were reacted together under reflux and water was removed by azeotropic distillation. Then, 23.5 g of dioctyl phthalate, 0.465 g of hydroquinone and 0.93 g of phosphorus pentoxide were added and depolymerization allowed to take place at 150°-210° C. under a reduced pressure tO afford 21.65 g of crude neopentyl α-cyanoacrylate. Redistillation thereof afforded (8.3 g of neopentyl α-cyanoacrylate (b.p. 65°-67° C./2 mmHg, m.p. 40°-41° C., yield 36%).
Reaction SMILES: C([Li])CCC.[C:6]([NH:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[O:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1.[NH4+].[Cl-]>C1COCC1>[C:9]([O:8][C:6](=[O:7])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:24]2([OH:27])[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)=[CH:16][CH:15]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1
Reactant: O=C1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C2(O)CCOCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
THF (50 mL) in an oven-dried 500 mL single neck flask was cooled in −78° C. bath under N2. A solution of n-butyllithium in hexanes (15.4 mL, 2.5 M, 38.6 mmol) was added dropwise via syringe over 10 min. The clear solution was stirred at −78° C. for 30 min. N-Boc-4-bromoaniline (5.00 g, 18.4 mmol), dissolved in 10 mL THF, was added dropwise over 10 min with stirring then stirred a further 30 min at −78° C. Tetrahydro-4H-pyran-4-one (2.02 g, 20.2 mmol) in 5 mL THF added was dropwise over 10 min. After 150 min, the reaction mixture was allowed to warm to RT then added to 200 mL saturated NH4Cl and extracted with ether (3×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and dried over MgSO4. Filtration and concentration provided the crude product that was recrystallized from 70 mL DCM to give the purified product as a white solid (2.29 g, 42%). MS (ESI): mass calcd. for C16H23NO4, 293.3; m/z found, 276.1 [M−H2O+H]+. 1H NMR (500 MHz, CDCl3): 7.46-7.38 (m, 2H), 7.36 (d, J=8.6 Hz, 2H), 6.48 (s, 1H), 3.90 (m, 4H), 2.30-1.98 (m, 2H), 1.68 (d, J=12.1 Hz, 2H), 1.52 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH:8]=[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=1[OH:23])([CH3:4])([CH3:3])[CH3:2].[C:24]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25]1>>[C:1]([C:5]1[CH:10]=[C:9]([N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:24]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:30])[CH:8]=[C:7]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=1[OH:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(Nc2cccc(Cl)c2)cc(C(C)(C)C)c1O
Reactant: O=C1CCC(=O)O1
Product: CC(C)(C)c1cc(N(C(=O)CCC(=O)O)c2cccc(Cl)c2)cc(C(C)(C)C)c1O
Temperature: 140 °C

Procedure:
A mixture of 1.50 g (0.0045 mole) of 2,6-di-tertiary-butyl-4-(3'-chloroanilino)phenol and 0.90 g (0.0090 mole) of succinic anhydride was heated under a nitrogen atmosphere at 140° C. for one hour. The resulting solid was recrystallized once from a mixture of ethanol and water and then twice from a mixture of ethyl acetate and hexane to hydroxyphenyl)-N-(3-chlorophenyl)carbamoyl]propionic acid, m.p. 204°-206° C. Analysis: Calculated for C24H30ClNO: % C, 66.7; % H, 7.0; % N, 3.2; Found: % C, 67.1; % H, 7.0; % N, 3.2.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]4)=[C:16]([F:33])[CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:4]1=[O:40])[CH3:2].[ClH:41]>C(OCC)(=O)C.C(OCC)C>[ClH:41].[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[C:16]([F:33])[CH:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:4]1=[O:40])[CH3:2]
Reactant: CCn1c(=O)c(-c2ccccc2)cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)c(F)c3)nc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCn1c(=O)c(-c2ccccc2)cc2cnc(Nc3ccc(N4CCNCC4)c(F)c3)nc21
Reaction time: 18 h
Yield: 87 %

Procedure:
To a stirred solution of tert-butyl 4-(4-(8-ethyl-7-oxo-6-phenyl-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)-2-fluorophenyl)piperazine-1-carboxylate (45 mg, 0.08 mmol) in ethyl acetate (5 mL) was added a 4M solution of hydrochloric acid in diethyl ether (5 mL) and the reaction was stirred for 18 h. The precipitate was filtered off to give 8-ethyl-2-(3-fluoro-4-(piperazin-1-yl)phenylamino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride as an off-white solid (36 mg, 0.07 mmol, 87%). ESMS m/z 445 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.21 (br. S., 1H), 9.22 (br. S., 2H), 8.85 (s, 1H), 8.02 (s, 1H), 7.84 (d, J=15. e.g., 1 Hz, 1H), 7.68 (d, J=7.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 1H), 7.43 (t, J=7.3 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 7.11 (t, J=8.5 Hz, 1H), 4.41 (q, J=6.7 Hz, 2H), 3.22 (br. S., 8H), 1.31 (t, J=6.7 Hz, 3H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[CH:15])=[CH:11][CH:12]=2)[C@H:7]([NH:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=2)[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2].CO.[N:28]([Si](C)(C)C)=[N+:29]=[N-:30]>[Cu]I.CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:28]=[N:29][NH:30][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=2)[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc2c(c1)[C@H](Nc1ccc(C#N)cn1)C[C@H](C)N2C(C)=O
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)N1c2ccc(-c3c[nH]nn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 100 °C

Procedure:
A microwaveable vial was charged with 6-(((2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 9) (527 mg, 1.595 mmol), Copper (I) Iodide (30 mg, 0.158 mmol), methanol (0.333 ml), DMF (3 ml). Azidotrimethylsilane (0.423 ml, 3.19 mmol) was added to the solution, the vial sealed and heated at 100° C. for 1 h (microwave). Azidotrimethylsilane (0.211 ml, 1.59 mmol) was added to the vial and the mixture heated for a further 1 h (sealed vial, microwave). Azidotrimethylsilane (0.211 ml, 1.590 mmol), and copper (I) iodide (30 mg, 0.158 mmol) was added. The vial was resealed and heated for a further 1 h. The reaction solution was concentrated in vacuo, diluted with water (15 ml) and extracted with DCM (3×10 ml). The organics were combined and dried (hydrophobic frit). The mixture was concentrated and the sample purified by chromatography on a silica cartridge (50 g) eluting with a methanol/DCM gradient (0-10%). The appropriate fractions were combined and the solvent evaporated in vacuo to give 6-(((2S,4R)-1-acetyl-2-methyl-6-(1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (50 mg). LCMS (formate): Rt 0.71 min, MH+ 374
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:20]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH2:16])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Cl.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:20]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:16][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(CN)c2cc(F)ccc2n1Cc1csc2ccc(F)cc12
Agent: Cl
Product: CCOC(=O)c1c(CNS(C)(=O)=O)c2cc(F)ccc2n1Cc1csc2ccc(F)cc12

Procedure:
3-Aminomethyl-5-fluoro-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester; salt with hydrogen chloride was reacted with methanesulfonyl chloride as described in Example 77.1. to give 5-fluoro-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-(methanesulfonylamino-methyl)-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give 5-fluoro-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-(methanesulfonylamino-methyl)-1H-indole-2-carboxylic acid as a colorless solid. MS: 449.3 ([M−H]−).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][C:17]=1[C:29]#[N:30].O[CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.O>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][C:17]=1[C:29]#[N:30]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1O
Reactant: CN1CCN(CCCO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCN1CCN(C)CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of diisopropyl azodicarboxylate (12.1 ml) in methylene chloride (50 ml) was added dropwise during 30 minutes to a stirred mixture of 4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline (12 g), 1-(3-hydroxypropyl)-4-methylpiperazine (9.7 g), triphenylphosphine (16.1 g) and methylene chloride (200 ml) that had been cooled to 5° C. The resultant mixture was allowed to warm to ambient temperature and was then stirred for 1 hour. Further portions of diisopropyl azodicarboxylate (1.2 ml) and triphenylphosphine (1.6 g) were added and the mixture was stirred at ambient temperature for a further 1 hour. The mixture was poured into water and the organic layer was separated, washed with a saturated brine solution, dried over magnesium sulphate and evaporated. The material so obtained was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the required starting material as a solid (14.5 g); NMR Spectrum: (DMSOd6) 1.95 (m, 2H), 2.13 (s, 3H), 2.24–2.5 (m, 10H), 4.0 (s, 3H), 4.25 (t, 2H), 7.43 (s, 1H), 7.51 (s, 1H), 8.95 (s, 1H); Mass Spectrum: M+H+ 375 and 377.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]1[O:19][C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[O:12][CH2:11]1>CN(C=O)C>[CH2:10]1[O:19][C:13]2([CH2:18][CH2:17][N:16]([C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[C:4]#[N:5])[CH2:15][CH2:14]2)[O:12][CH2:11]1
Reactant: N#Cc1ccccc1F
Reactant: C1CC2(CCN1)OCCO2
Solvent: CN(C)C=O
Product: N#Cc1ccccc1N1CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
A solution of 2-fluorobenzonitrile (2.75 g, 22.7 mmol) and 4-piperidone ethylene ketal (4.25 g, 29.7 mmol) in DMF (40 mL) was heated to 120° C. for 4 h. The resulting mixture was cooled to room temperature overnight. The solvent was removed in vacuo and the residue dissolved in ether and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of ether and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound (4). The crude product was used directly.