Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]1[CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1(C)OC(=O)CC(=O)[O:18]1.C(Cl)Cl.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH:13]1([C@H:9]2[C:10](=[O:12])[CH2:16][C:17](=[O:18])[N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C1CC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)CC(=O)[C@@H]1C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(tert-Butoxycarbonylamino)-2-cyclopropylacetic acid (13) (5.47 g, 25.4 mmol), Meldrum's acid (14) (4.02 g, 27.9 mmol), and DMAP (4.34 g, 35.56 mmol) were added to CH2Cl2 (100 mL) under nitrogen at 0° C. After 30 minutes EDAC (6.81 g, 35.56 mmol) was added. The reaction was stirred 16 hr at rt and poured into EtOAc (300 mL), washed with brine (200 ml), 5% citric acid (300 mL), and again brine (200 mL). The organic phase was then refluxed for 1 hr. The mixture was evaporated to give (S)-tert-butyl 2-cyclopropyl-3,5-dioxopyrrolidine-1-carboxylate (15) a yellow oil (4.0 g, 69%) that was taken into the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(O)C.[BH4-].[Na+]>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1ccncc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1ccncc1Cl
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a mixture of 1.53 g of 3-chloroisonicotinaldehyde and 5 ml of ethanol was gradually added 0.40 g of sodium borohydride under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour, and subsequently at room temperature for 1 hour. Saturated brine was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and dried over magnesium sulfate. The resulting mixture was concentrated under reduced pressure to obtain 1.40 g of (3-chloropyridin-4-yl)methanol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4](=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:5][OH:6].[CH:11]([N:14]([P:18](N(C(C)C)C(C)C)Cl)[CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12]>C1COCC1>[CH:11]([N:14]([CH:15]([CH3:17])[CH3:16])[P:18]1[O:6][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[CH2:2][O:1]1)([CH3:13])[CH3:12]
Reactant: OCc1ccccc1CO
Reactant: CC(C)N(C(C)C)P(Cl)N(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)N(C(C)C)P1OCc2ccccc2CO1

Procedure:
Phthalyl alcohol (1.15 g, 8.31 mmol) was dissolved in 5 ml of THF, and bisdiisopropylaminochlorophosphine (2.21 g, 8.31 mmol) which was dissolved in 5 ml of THF was added dropwise to the solution at -15° C. under a nitrogen atmosphere. Afterward, the temperature of the solution was adjusted to room temperature, and after the disappearance of phthalyl alcohol had been confirmed, hydrochloride of diisopropylamine was washed with ether. The wash liquor was concentrated and then distilled in order to obtain the desired product having a melting point of from 150° to 155° C. (0.7 mmHg).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(O)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine (0.620 g, 2.69 mmol), (4-hydroxy-phenyl)-acetic acid (0.242 g, 5.15 mmol), HATU (1.23 g, 3.23 mmol) and diisopropylethylamine (0.939 mL, 5.39 mmol) in 9 mL of DMF was stirred at room temperature for 6 hours, concentrated under reduced pressure and the residue dissolved in ethyl acetate and washed with aqueous NaHCO3 (×3), brine (×2), and water. The organic layer was dried (Na2SO4), filtered, concentrated under reduced pressure and the residue purified by flash chromatography (60–90% ethyl acetate (1% triethylamine) in hexanes) to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.62 (m, 4 H), 2.45 (m, 4 H), 2.83 (t, J=6.78 Hz, 2 H), 3.53 (d, J=5.76 Hz, 2 H), 4.38 (t, J=6.78 Hz, 2 H), 6.71 (m, 2 H), 7.13 (m, 3 H), 7.64 (m, 1 H), 7.94 (s, 1 H), 8.13 (m, 1 H), 9.25 (s, 1 H), 10.24 (s, 1 H); MS (ESI) m/z 365 [M+H]+.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[C:8]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:13]=[CH:12][C:11]([C:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:15][CH2:16][NH2:17])=[CH:10][CH:9]=1>C(O)=O>[C:21]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]=[CH:19][C:18]([C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:9][CH:10]=2)=[CH:15][CH2:16][NH:17][CH:5]=[O:7])=[CH:23][CH:22]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCC=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Solvent: O=CO
Product: O=CNCC=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1

Procedure:
Acetic anhydride (1ml) was added to a solution of 1, 1 -di(4-biphenylyl)- 3 -amino-prop-1-ene (1g) in 99% formic acid (5ml) and the mixture was refluxed for 1 hour then poured onto ice. The solid was collected, washed with water, dried and then recrystallised from benzene/ n - propanol to furnish 1, 1-di (4 -biphenyly)-3-formamido-prop-1-ene (m.p. 171°- 173° C). This compound, reduced with lithium aluminium/hydride in ether/tetrahydrofuran at - 30° C, afforded 1, 1-di(4-biphenylyl)-3-methylamino-prop- 1-ene identical with that described in Example 4.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]2[O:6][C:7]3[CH:25]=[CH:24][CH:23]=[CH:22][C:8]=3[C@@H:9]3[C@H:14]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1>CN(C=O)C.[Pd]>[C@H:14]1([NH:15][C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[C@@H:9]2[N:10]([C:4]3[CH:3]=[CH:2][CH:27]=[CH:26][C:5]=3[O:6][C:7]3[CH:25]=[CH:24][CH:23]=[CH:22][C:8]=32)[CH2:11][CH2:12][CH2:13]1
Reactant: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12)C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CCCN2c3ccccc3Oc3ccccc3[C@H]12)C(F)(F)F
Reaction time: 48 h
Yield: 98.2 %

Procedure:
10 mg Pd/C 10% was added to a solution of trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (100 mg, 0.25 mmol) in 5 mL of DMF. The suspension was shaken under H2 atmosphere for 2 days. The mixture was filtered, poured into water and extracted with diethyl ether. The organic layer was washed with water, dried (Na2SO4) and evaporated to give trans-N-(2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (89 mg, 98%). Data: 1H-NMR (400 MHz, CDCl3) 1.85 (m, 3H), 2.99 (m, 1H), 3.18 (m, 1H), 3.75 (m, 1H), 4.50 (d, J=8,1H), 4.72 (m, 1H), 6.62 (br, 1H), 6.84-7.30 (8 arH). (m/z)=362 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH2:11])[CH2:6]1.[F:14][CH:15]([F:26])[C:16]1[C:20]([C:21](Cl)=[O:22])=[C:19]([F:24])[N:18]([CH3:25])[N:17]=1>>[F:26][CH:15]([F:14])[C:16]1[C:20]([C:21]([NH:11][CH:7]2[CH2:8][CH2:9][CH2:10][CH:5]([CH2:4][CH2:3][C:2]([CH3:13])([CH3:12])[CH3:1])[CH2:6]2)=[O:22])=[C:19]([F:24])[N:18]([CH3:25])[N:17]=1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Reactant: CC(C)(C)CCC1CCCC(N)C1
Product: Cn1nc(C(F)F)c(C(=O)NC2CCCC(CCC(C)(C)C)C2)c1F
Yield: 54 %

Procedure:
As for example 1—step 6, condensation of 0.50 g 3-(3,3-dimethylbutyl)cyclohexanamine over 0.638 g of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride gives 0.65 (54% of theory) of 3-(difluoromethyl)-N-[3-(3,3-dimethylbutyl)cyclohexyl]-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide. log P=4.80.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: ClCCN1CCCC1
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1C(C)N(CCN2CCCC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=597.1 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and 1-(2-chloroethyl)-pyrrolidine.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1)=O>O1CCCC1>[Br:13][C:9]1[CH:8]=[C:7]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([Cl:25])[CH:18]=2)=[CH2:14])[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)c1
Reactant: COc1ccc(C(C)=O)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(c1cccc(Br)c1)c1ccc(OC)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium (1.6 M in hexane, 19.5 mL, 31.3 mmol, 1.16 eq.) was added dropwise over 20 min to a solution of 1,3-dibromobenzene (3.59 mL, 29.7 mmol, 1.1 eq) in 30 mL of dry tetrahydrofuran at −78° C. and under an inert atmosphere. The white suspension formed was stirred at −78° C. for 30 min. A solution of 3-chloro-4-methoxyacetophenone (5 g, 27 mmol, 1.0 eq.) in 20 mL of tetrahydrofuran was then added dropwise and the reaction stirred for 1 h. The reaction mixture was examined by LC-MS which showed the complete formation of tertiary alcohol. The solution was quenched with a saturated solution of ammonium chloride and water. 2 N HCl was then added to reach pH=5. The two phases were separated; the organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual material (tertiary alcohol) was dissolved in a mixture of acetic acid/sulfuric acid (10 mL of acetic acid, 0.3 mL of sulfuric acid) and the reaction mixture was stirred for 3 h at room temperature; then it was examined by LC-MS which showed the complete formation of desired product. The solution was quenched with ice and dichloromethane (20 mL) was added. The two phases formed and were separated. The organic layer was washed with a saturated solution of sodium bicarbonate and brine. It was then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crude was purified by flash chromatography eluting with cyclohexane/ethyl acetate (gradient 0-4%). The desired product was obtained as a yellow oil (4.36 g, Yield: 50%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][C:8](=[O:19])[NH:7][C:6]=2[CH:20]=1.Cl[C:24]1[N:29]=[C:28]([NH:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]2[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:27]([Cl:42])=[CH:26][N:25]=1.Cl.O1CCOCC1>COCCO>[CH2:12]([N:10]1[CH2:11][C:5]2[CH:4]=[C:3]([O:21][CH3:22])[C:2]([NH:1][C:24]3[N:29]=[C:28]([NH:30][C@@H:31]4[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]4[NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[C:27]([Cl:42])=[CH:26][N:25]=3)=[CH:20][C:6]=2[NH:7][C:8](=[O:19])[CH2:9]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc2c(cc1N)NC(=O)CN(Cc1ccccc1)C2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)NC(=O)CN(Cc1ccccc1)C2
Temperature: 25 °C

Procedure:
To a solution of 8-amino-4-benzyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (55 mg, 0.19 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (63 mg, 0.19 mmol) in 2-methoxyethanol (2 mL) was added 4N HCl-dioxane (0.20 mL). The mixture was heated to reflux for two hours whereupon LCMS showed complete consumption of the aniline. After being cooled to room temperature, triethylamine was added to pH 9 and the crude product was purified by preparative tlc (5% MeOH-DCM) to afford N-{(1R,2R)-2-[2-(4-benzyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-5-chloro-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a mustard yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.96 (s, 2H), 7.73 (s, 1H), 7.35 (m, 5H), 7.05 (d, J=7 Hz, 1H), 6.93 (s, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.55 (m, 1H), 3.86 (s, 3H), 3.70 (s, 2H), 3.64 (s, 2H), 3.06 (s, 2H), 2.88 (s, 3H), 1.97 (m, 2H), 1.63 (m, 2H), 1.38 (m, 2H), 1.23 (m, 2H); MS (m/e) 601 (M+1); mp 214° C. (dec.).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.[Cl:18][C:19]1[C:24]([CH:25]=[CH:26][C:27](O)=[O:28])=[CH:23][CH:22]=[C:21]([C:30]([F:33])([F:32])[F:31])[N:20]=1>>[Cl:18][C:19]1[C:24]([CH:25]=[CH:26][C:27]([NH:2][CH2:3][C:4]2[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=2)=[O:28])=[CH:23][CH:22]=[C:21]([C:30]([F:31])([F:32])[F:33])[N:20]=1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: Cl
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc(F)c1NS(C)(=O)=O
Yield: 89.9 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (228 mg, 0.795 mmol) was reacted with 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (200 mg, 0.795 mmol) to give the title compound (340 mg, 90%).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].Br[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[N:11]=1>O1CCCC1>[C:17]1([CH3:24])[CH:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[C:16]=1[C:12]1[N:11]=[C:10]([CH2:7][C:6]#[N:8])[CH:15]=[CH:14][CH:13]=1
Reactant: CC#N
Reactant: Cc1cc(C)c(-c2cccc(Br)n2)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(-c2cccc(CC#N)n2)c(C)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 40.9 %

Procedure:
n-Butyllithium (2.5M, 19.1 mL, 47.8 mmol) was added to tetrahydrofuran (135 mL) and the solution was cooled to −78° C. Acetonitrile (2.5 mL, 47.8 mmol) was then added dropwise and the reaction stirred for 45 min. 2-Bromo-6-mesitylpyridine (2.00 g, 7.24 mmol) was added as a solution in 10 mL of tetrahydrofuran. The reaction continued to stir at −78° C. for 0.5 hr and was then warmed to room temperature for 1 h. The reaction was quenched with water and extracted with ethyl acetate, dried, and concentrated. Flash chromatography (20% ethyl acetate/hexanes) gave 0.70 g (41% yield) of the desired product as an orange oil.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.Cl.[NH2:17][CH2:18][C:19](O)=[O:20].[NH2:22][C:23]1[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][C:24]=1[C:25](=[N:33][CH2:34][CH2:35][OH:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32]>CN(C)C=O.O.O1CCCC1>[NH2:17][CH2:18][C:19]([NH:22][C:23]1[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][C:24]=1[C:25](=[N:33][CH2:34][CH2:35][OH:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])=[O:20]
Reactant: Nc1ccc(Br)cc1C(=NCCO)c1ccccc1F
Reactant: NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: NCC(=O)Nc1ccc(Br)cc1C(=NCCO)c1ccccc1F
Yield: 57.9 %

Procedure:
To a solution of 4.5g of N,N'-dicyclohexylcarbodiimide in 100ml of dimethylformamide is added a solution of 2.2g of glycine hydrochloride in 2.2ml of water in a period of about 30 seconds under stirring and ice-cooling. Immediately a solution of 3.4g of 2-{[2-amino-5-bromo-α-(2-fluorophenyl)benzylidene]amino}ethanol in 10ml of tetrahydrofuran is added dropwise to the reaction mixture, and the mixture is stirred for further 3 hours at room temperature. After completion of the reaction, one liter of water is added to the reaction mixture which is extracted once with 100ml and four times with 50ml of benzene. The organic layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off to give an oily substance, which is purified by chromatography of alumina column and then recrystallized from benzene-n-hexane (3:2 in volume) mixture yielding 2.3g of the desired product melting at 167°-168° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[NH:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]
Reactant: O[C@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 243.1 (20 h at 90° C.+3 h at 105° C.) using 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide and (3S,4S)-pyrrolidine-3,4-diol to afford a white amorphous solid. UPLC-MS (Condition 3) tR=1.01 min, m/z=476.8 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[S:15][CH3:16])=O.COC1C=CC(/C=[C:32]2/[C:33]([NH:35][C:36]([S:38]/2)=[NH:37])=[O:34])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:37][C:36]1[S:38]/[C:32](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[S:15][CH3:16])/[C:33](=[O:34])[N:35]=1
Reactant: CSc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CSc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 38 was used, starting from 6-formyl-4-methylsulfanyl-quinoline-3-carbonitrile (example 55b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-methylsulfanyl-quinoline-3-carbonitrile. LC-MS m/e 327 (MH+).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[Cl:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][C:14]2[N:19]=[C:18]([OH:20])[C:17]([NH:21][C:22](=O)[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[C:16]([OH:31])[N:15]=2)=[CH:11][CH:10]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]2[NH:19][C:18](=[O:20])[C:17]3[N:21]=[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[O:31][C:16]=3[N:15]=2)=[CH:32][CH:33]=1
Reactant: O=C(Nc1c(O)nc(Cc2ccc(Cl)cc2)nc1O)c1cccc(F)c1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1[nH]c(Cc2ccc(Cl)cc2)nc2oc(-c3cccc(F)c3)nc12
Temperature: 60 °C
Reaction time: 20 h
Yield: 6.1 %

Procedure:
7.4 g of phosphorus pentachloride were added at 60° C. to a suspension of 8.9 g of N-[2-(4-chloro-benzyl)-4,6-dihydroxy-pyrimidin-5-yl]-3-fluoro-benzamide hydrochloride in 100 ml of dry chloroform. After heating at 60° C. for several hours, 5.5 g of phosphorus oxychloride were added and the reaction mixture was stirred at 75° C. for 20 h. After cooling to room temperature, the precipitate was filtered off and purified by silica gel chromatography (gradient from ethyl acetate to dichloromethane to dichloromethane/methanol 3:1). The product fractions were evaporated and the residue washed with chloroform and water and dried in an infrared dryer until constant weight to give 0.47 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[C:25](=[O:31])[N:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1>>[CH3:30][N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)[C:25]1=[O:31]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: Cn1cccc(Br)c1=O
Product: Cn1cccc(N2CCC3(CC2)CCN(c2ccc(OC(F)(F)F)cc2)C3=O)c1=O

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 3-bromo-1-methyl-1H-pyridin-2-one. Light yellow solid. MS (ESI): 422.1 (MH+)
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=2)=[O:12])[C:4](=[O:28])[CH:3]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([O:39][C:40]([F:43])([F:42])[F:41])=[C:34](B(O)O)[CH:35]=1>>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([O:39][C:40]([F:41])([F:42])[F:43])=[C:34]([C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[CH:16][CH:15]=3)=[O:12])[C:4](=[O:28])[CH:3]=2)[CH:35]=1
Reactant: OB(O)c1cc(Cl)ccc1OC(F)(F)F
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(Br)cc1=O
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2OC(F)(F)F)cc1=O

Procedure:
127 mg (purity 70%, 0.2 mmol) of tert-butyl 4-{[2-(4-bromo-5-cyano-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate) and 58 mg (0.24 mmol) of 5-chloro-2-trifluoromethoxyphenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. Yield: 107 mg (purity 94%, 89% of theory)
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4].[NH2:30][CH2:31][CH:32]([OH:34])[CH3:33]>>[CH2:1]([N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:30][CH2:31][CH:32]([OH:34])[CH3:33])=[O:25])[C:6]1=[O:29])[CH2:2][CH2:3][CH3:4]
Reactant: CC(O)CN
Reactant: CCCCn1c(=O)c(C(=O)OCC)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Product: CCCCn1c(=O)c(C(=O)NCC(C)O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 38 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-butyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.050 mmol) and 1-amino-2-propanol (0.05 mL), was prepared 1-butyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (8 mg, 38% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.50 (br s, 1 H), 8.57 (s, 1 H), 7.28 (s, 1 H), 7.19-7.15 (m, 2 H), 7.07-7.02 (m, 2 H), 4.14 (s, 2 H), 4.11-4.07 (m, 3 H), 3.61 (m, 1 H), 3.39 (m, 1 H), 1.57-1.49 (m, 2 H), 1.38-1.24 (m, 6 H), 0.91 (m, 3 H); MS m/z 428 (M+1).