Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([CH3:11])=[N:7]1)C.O.[NH2:14][NH2:15]>C(O)C>[CH3:11][C:8]1[CH:9]=[CH:10][N:6]([CH2:5][C:4]([NH:14][NH2:15])=[O:3])[N:7]=1
Reactant: NN
Reactant: CCOC(=O)Cn1ccc(C)n1
Solvent: O
Solvent: CCO
Product: Cc1ccn(CC(=O)NN)n1
Temperature: 25 °C
Yield: 95 %

Procedure:
As described for example 112a, (3-methyl-pyrazol-1-yl)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture was heated under reflux for 4 h. The mixture was then cooled to rt and the precipitated product was filtered off and crystallized from ethanol. The title compound (>95% purity) was obtained as a white solid (yield: 68%). 1H-NMR (300 MHz, DMSO): δ=2.12 (s, 3H), 4.29 (s, 2H), 4.60 (s, 2H), 6.00 (d, J=2 Hz, 1H), 7.55 (d, J=2 Hz, 1H), 9.26 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:15][CH3:16])[CH:12]([OH:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:15]([CH:11]1[C:5]2[C:6](=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:23]([C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[C:20]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:21]=2)[O:14][CH:12]1[CH3:13])[CH3:16]
Reactant: CCC(c1ccc(OC)c(OC)c1)C(C)O
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Product: CCC1c2cc(OC)c(OC)cc2C(c2ccc(OC)c(OCc3ccccc3)c2)OC1C

Procedure:
Reaction of 3-(3,4-dimethoxyphenyl)pentan-2-ol with 4-methoxy-3-(phenyl-methoxy)benzaldehyde to yield 4-(4-ethyl-6,7-dimethoxy-3-methyliso-chromanyl)-1-methoxy-2-(phenylmethoxy)benzene.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11]Cl)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[C-:13]#[N:14].[Na+].O>CS(C)=O>[CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:13]#[N:14])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: [C-]#N
Reactant: CCCC[C@H]1CC[C@H](CCl)CC1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCC[C@H]1CC[C@H](CC#N)CC1
Temperature: 140 °C

Procedure:
In 40 cm3 of DMSO, 38 g (0.20 mol) of trans-4-butyl cyclohexylchloromethane and 12 g (0.24 mol) of NaCN were stirred and heated with a mantle heater to 140° C. The reaction product was cooled to room temperature, combined with 100 cm3 of water, extracted with chloroform, and washed with water. The chloroform was distilled off. The oily residue was subjected to vacuum distillation (b.p. 90° C./3 mmHg) to yield 34 g (0.19 mol) of trans-4-butylcyclohexyl acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH2:7][CH3:8])[NH:4][N:3]=1.CS[C:11](=[N:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[CH3:12]>O1CCOCC1>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:14]1[N:3]2[N:4]=[C:5]([CH2:7][CH3:8])[CH:6]=[C:2]2[N:1]=[C:11]([CH3:12])[N:13]=1
Reactant: CCc1cc(N)n[nH]1
Reactant: CSC(C)=NC(=O)c1ccc(Cl)cc1Cl
Solvent: C1COCCO1
Product: CCc1cc2nc(C)nc(-c3ccc(Cl)cc3Cl)n2n1
Temperature: 25 °C
Yield: 13.7 %

Procedure:
A mixture of 3-amino-5-ethylpyrazole (10.3 g, 39.3 mmol) and N-(1-(methylthio)ethylidene)-2,4-dichloro-benzamide (4.0 g, 35.7 mmol) in anhydrous dioxan (20 mL) was stirred at reflux temperature under a nitrogen atmosphere for 16 h. After being cooled to ambient temperature, the reaction mix was concentrated in vacuo and the residue was treated with dichloromethane. The resulting suspension was filtered and the filtrate was concentrated in vacuo to afford an oil (1.5 g, 14% yield): NMR (CDCl3, 300 MHz): δ 7.62 (d, 1H, J=8), 7.59 (d, 1H, J=2), 7.45 (dd, 1H, J=8,2), 6.42 (s, 1H), 2.82 (q, 2H, J=8), 2.73 (s, 3H), 1.30 (t, 3H, J=8).
Reaction SMILES: [CH3:1][C@:2]1([NH:7]C(=O)OC(C)(C)C)[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[C:22]([C:24]1[C:29]2[N:30]=[C:31]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[O:32][C:28]=2[C:27](F)=[C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:25]=1[CH3:45])#[N:23]>CS(C)=O>[NH2:7][C@@:2]1([CH3:1])[CH2:6][CH2:5][N:4]([C:27]2[C:28]3[O:32][C:31]([C:33]([N:35]([CH3:36])[CH3:37])=[O:34])=[N:30][C:29]=3[C:24]([C:22]#[N:23])=[C:25]([CH3:45])[C:26]=2[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@](C)(N)C2)c2oc(C(=O)N(C)C)nc2c1C#N
Temperature: 150 °C
Yield: 41.6 %

Procedure:
A dimethyl sulfoxide (1 ml) solution of tert-butyl [(3S)-3-methylpyrrolidin-3-yl]carbamate (I-345) (300 mg, 1.50 mmol) and triethylamine (244 μl, 1.75 mmol) was added to a dimethyl sulfoxide (6 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (404 mg, 1.25 mmol) stirred in an oil bath at 150° C., followed by stirring in an oil bath at 150° C. for 30 minutes. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with aqueous 10% citric acid solution, water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1→1:2, v/v). The obtained yellow foamy substance was dissolved in dichloromethane (5 ml), and with cooling with ice, trifluoroacetic acid (10 ml) was added, followed by stirring at room temperature for 5 hours. The reaction liquid was concentrated under reduced pressure, then an aqueous saturated sodium hydrogencarbonate solution and water were added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v), and the obtained eluate was purified in slurry with isopropyl ether to obtain the entitled compound (210 mg, 41%) as a pale yellow solid.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11](Cl)=[C:10]([O:15][CH3:16])[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[C:1]1([N:7]2[C:12](=[O:13])[C:11]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)=[C:10]([O:15][CH3:16])[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cnn(-c2ccccc2)c(=O)c1Cl
Reactant: OB(O)c1ccc(F)cc1
Product: COc1cnn(-c2ccccc2)c(=O)c1-c1ccc(F)cc1
Yield: 96 %

Procedure:
The 2-phenyl-4-chloro-5-methoxy-3(2H)-pyridazinone product was coupled with 4-fluorophenylboronic acid according to the method of Example 6 to provide 2-phenyl-4-(4-fluorophenyl)-5-methoxy-3(2H)-pyridazinone (yield: 1.1 g; 96%). 1H NMR (300 MHz, CDCl3) δ 4.00 (s, 3H), 7.10 (t, J=9 Hz, 2H), 7.45 (m, 3H), 7.60 (m, 4H), 8.06 (s, 1H). MS (DCI/NH3) m/z 297 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[F:18])[C:5]2=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)(=[O:29])=[O:28]>>[F:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[C:10]1[C:5]2[C:6](=[N:7][C:2]([NH:36][CH:33]3[CH2:34][CH2:35][N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:31][CH2:32]3)=[N:3][CH:4]=2)[NH:8][N:9]=1
Reactant: Fc1cccc(F)c1-c1n[nH]c2nc(Cl)ncc12
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2ncc3c(-c4c(F)cccc4F)n[nH]c3n2)CC1
Yield: 34.5 %

Procedure:
The compound was prepared from 6-chloro-3-(2,6-difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 8) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoro-acetic acid in an analogous manner as described in Example 4 and was purified by HPLC (Gilson) to give a free base (34.5% yield). MS (M+H)+, 409.22.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:7])[O:5][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:12](Cl)(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]>C(Cl)Cl>[C:12]([C:6]1[O:5][C:4](=[O:7])[NH:3][C:2]=1[CH3:1])(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Cc1coc(=O)[nH]1
Reactant: CCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(=O)c1oc(=O)[nH]c1C
Temperature: 0 °C
Yield: 39.1 %

Procedure:
Six grams (0.06 mol) of 4-methyl-2(3H)-oxazolone and 24.2 g (0.182 mol) aluminum chloride were suspended in 250 ml methylene chloride. To this mixture was added dropwise 8.3 g (0.069 mol) n-pentanoyl chloride. The mixture was stirred and refluxed 15 hours, cooled and poured into ice water. The methylene chloride layer was isolated, washed with sodium bicarbonate solution and water. The methylene chloride solution was dried and solvent evaporated to give a residue which was recrystallized two times from ethyletherpentane to give 4.3 g (39%) of title compound; m.p. 92°-94°.
Reaction SMILES: N#N.[OH-].[Na+].[C:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)(=[O:7])[CH3:6].Br[CH2:17][CH2:18][CH2:19][Cl:20]>C(O)C>[C:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:17][CH2:18][CH2:19][Cl:20])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: ClCCCBr
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)Nc1ccc(OCCCCl)cc1

Procedure:
In a round bottomed flask equipped with magnetic stirring, reflux condenser, and N2 atmosphere was placed ethanol (500 ml), sodium hydroxide (15.0 g), 4-acetamidophenol of Formula XXIII (30.0 g), and 1-bromo-3-chloropropane of Formula XXII (47.0 g) and the mixture was refluxed overnight. Upon cooling off-white crystals were deposited and then collected. The mother liquor was evaporated to dryness and dissolved in CH2Cl2 then washed with H2O, dried, and concentrated to 50 ml. A second crop of crystals were deposited. These were combined with the first crop of crystals and recrystallized from ethanol to give colorless crystals (20.3 g), mp 128°-130° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[Cl:20][C:21]1[CH:22]=[C:23]([OH:31])[C:24](=[CH:29][CH:30]=1)[C:25]([NH:27]O)=[O:26]>O1CCCC1>[Cl:20][C:21]1[CH:30]=[CH:29][C:24]2[C:25]([OH:26])=[N:27][O:31][C:23]=2[CH:22]=1
Reactant: O=C(NO)c1ccc(Cl)cc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Oc1noc2cc(Cl)ccc12

Procedure:
A solution of 1,1'-carbonyldiimidazole (12.76 g, 78.5 mmol) and triethylamine (12.6 mL, 90 mmol) in tetrahydrofuran is slowly added to a refluxing suspension of 4-chlorosalicylohydroxamic acid (13.39 g, 71.4 mmol) in tetrahydrofuran. The reaction mixture is refluxed for 1 hour, cooled, concentrated in vacuo, diluted with water, acidified with concentrated hydrochloric acid (pH1) and filtered to obtain a solid. A solution of the solid in ether is extracted with saturated sodium hydrogen carbonate solution. The combined aqueous extracts are acidified with concentrated hydrochloric acid and the resultant precipitate is collected and dried overnight to give the title product as a white solid, mp 218°-219° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: N#Cc1ccc(COc2ccc(Cl)c([N+](=O)[O-])c2)cc1

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 4-Bromomethyl-benzonitrile using the conditions described in Example 10C to provide 4-(4-Chloro-3-nitro-phenoxymethyl)-benzonitrile which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][O:35][CH2:36][CH2:37][NH:38][CH3:39]>>[CH3:34][O:35][CH2:36][CH2:37][N:38]([CH3:39])[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CNCCOC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COCCN(C)c1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide with cesium carbonate and N-(2-methoxyethyl)methylamine. ES-MS m/e (%): 457 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:18][CH2:17][N:16]3[C@H:11]([CH2:12][O:13][CH2:14][CH2:15]3)[CH2:10]2)[C:3]=1[F:19].O.[NH2:21][NH2:22]>O1CCOCC1>[F:19][C:3]1[C:4]([N:9]2[CH2:18][CH2:17][N:16]3[C@H:11]([CH2:12][O:13][CH2:14][CH2:15]3)[CH2:10]2)=[N:5][C:6]([CH3:8])=[N:7][C:2]=1[NH:21][NH2:22]
Reactant: NN
Reactant: Cc1nc(Cl)c(F)c(N2CCN3CCOC[C@@H]3C2)n1
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(NN)c(F)c(N2CCN3CCOC[C@@H]3C2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of (9aS)-8-(6-chloro-5-fluoro-2-methyl-4-pyrimidinyl)octahydropyrazino[2,1-c][1,4]oxazine (assumed 31.03 g, 108.2 mmol) in dioxane (430 mL) was added hydrazine monohydrate (31 mL). The mixture was heated and stirred at 80° C. overnight, and then at 85° C. for 7 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (500 mL) and washed with saturated aq. NaHCO3 (200 mL). The aqueous phase was extracted with a fresh portion of DCM (100 mL), and this organic phase was washed with saturated aq. NaHCO3 (100 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and dried under high vacuum overnight to provide (9aS)-8-(5-fluoro-6-hydrazino-2-methyl-4-pyrimidinyl)octahydropyrazino[2,1-c][1,4]oxazine (27.98 g, 92% yield for 2 steps) as a light yellow solid. LCMS: (M+H)+: 283.3.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[NH3:13]>CN(C)C=O.O>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH2:13])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: N
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(N)n1
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of 2-chloro-6-methoxy-3-nitropyridine (25.3 g, 0.134 mol) and a concentrated aqueous ammonia solution (70 ml) in N,N-dimethylformamide (200 ml) was stirred at 70° C. for 4 hours and 15 minutes. The reaction mixture was cooled to room temperature and then diluted with water. The resulted precipitate was collected by filtration to yield the title compound (16.8 g, 99.2 mmol, 74.0%) as a yellow solid.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:26]2[CH:25]=[C:24]([CH3:27])[N:23]=[C:22]([NH2:28])[C:21]=2[N:20]=[C:19]1[CH2:29][O:30][CH2:31][CH3:32]>>[NH2:28][C:22]1[C:21]2[N:20]=[C:19]([CH2:29][O:30][CH2:31][CH3:32])[N:18]([CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]([NH:10][C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:12])[C:26]=2[CH:25]=[C:24]([CH3:27])[N:23]=1
Reactant: CCOCc1nc2c(N)nc(C)cc2n1CCCCN
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Product: CCOCc1nc2c(N)nc(C)cc2n1CCCCNC(=O)N[C@@H]1C[C@H]1c1ccccc1

Procedure:
Using the method of Examples 36-45, trans-2-phenylcyclopropyl isocyanate was reacted with 1-(4-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 437.2666.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([CH2:30][OH:31])[CH2:20][CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][C@H:12]1[CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33]I>>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([CH2:30][O:31][CH3:33])[CH2:20][CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][C@H:12]1[CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN([C@H](CO)CCOCc2ccccc2)C(=O)CCN1C(=O)OCc1ccccc1
Reactant: CI
Product: COC[C@H](CCOCc1ccccc1)N1C[C@@H](C)N(C(=O)OCc2ccccc2)CCC1=O

Procedure:
In analogy to the procedure described in intermediate 6B, (R)-4-((S)-3-benzyloxy-1-hydroxymethyl-propyl)-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester and methyl iodide gave the title compound in quantitative yield as white oil. MS: 455.4 (MH+).
Reaction SMILES: [N:1]1([C:6]2[CH:28]=[CH:27][C:9]([CH2:10][N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=S)[C:13]([C:22]([O:24]CC)=O)=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:29][NH2:30]>C(O)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][N:11]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:14]4=[N:29][NH:30][C:22](=[O:24])[C:13]4=[N:12]3)=[CH:27][CH:28]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: NN
Reactant: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2ccccc2c1=S
Solvent: CCO
Product: O=c1[nH]nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)nc1-2
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Ethyl 1-[4-(1H-pyrazol-1-yl)benzyl]-4-thioxo-1,4-dihydrocinnoline-3-carboxylate [(Example 31, Step 4) 449 mg, 1.15 mmol] was dissolved in ethanol (12.0 mL) and treated with hydrazine (0.61 mL, 19.57 mmol, 17 equiv). The mixture was stirred at 70° C. for 30 minutes then cooled to ambient temperature and concentrated in vacuo. The residue was suspended in ethyl acetate and filtered. The resulting solid was washed with dichloromethane and dried under in vacuo to afford the titled compound as a dark red powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4](F)[CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Reactant: C1CNCCN1
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1cc(Br)cc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-bromo-3-fluoro-5-(trifluoromethyl)-benzene (100 g, 0.41 moles), piperazine (194.9 g, 2.26 moles) in DMSO (800 ml) was heated at 100° C. for 5 hours, cooled at room temperature and stirred overnight. The mixture was poured into water and the yellow solid which separeted was filtered. The solid was suspended in a 5% THF solution in water (300 ml) water/THF, stirred for 1 hour and filtered again.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([NH2:36])=[CH:29][C:28]=2[CH:37]([CH3:39])[CH3:38])=[O:25])[C:6]1=[O:40])[CH2:2][CH2:3][CH3:4].[CH:41](=O)[C:42]1[CH:47]=[CH:46][CH:45]=[N:44][CH:43]=1.Cl.[BH4-].[Na+]>CO.O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([NH:36][CH2:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[CH:29][C:28]=2[CH:37]([CH3:39])[CH3:38])=[O:25])[C:6]1=[O:40])[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1cccnc1
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(N)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(NCc3cccnc3)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-(2,6-diisopropyl-4-aminophenyl)urea (450 mg, 0.727 mmol) in methanol (5 ml) are added nicotinaldehyde (0.137 ml, 1.45 mmol) and conc. hydrochloric acid (0.12 ml, 1.44 mmol) at room temperature. Then, the mixture is cooled under ice-cooling, and thereto is added sodium borohydride (68.6 mg, 1.09 ml), and the mixture is stirred at room temperature for 5 hours. To the mixture is added water, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with an aqueous sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound (475 mg, 0.654 mmol) as colorless amorphous.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([O-:8])=O)[CH3:2].[K+].C(N(CC)CC)C.[Mg+2].[Cl-].[Cl-].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH:32]2[CH2:34][CH2:33]2)=[C:26]([CH:30]=1)C(Cl)=O>C(#N)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH:32]2[CH2:34][CH2:33]2)=[C:26]([C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])[CH:30]=1
Reactant: O=C(Cl)c1cc(Cl)ccc1OC1CC1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC1CC1
Temperature: 0 °C
Yield: 88.6 %

Procedure:
Acetonitrile (200 mL) was added to potassium 3-ethoxy-3-oxopropanoate (31.1 g, 182.7 mmol), in a 1000 mL 3-necked flask under N2 with stirring. The reaction mixture was cooled to 0° C., then triethylamine (38.8 mL, 278.4 mmol) was added, followed by MgCl2 (20.71 g, 217.5 mmol). The reaction mixture was warmed to room temperature and stirred for an additional 2.5 h. The resulting slurry was cooled to 0° C. and 5-chloro-2-cyclopropoxybenzoyl chloride (18.5 g, 87 mmol) was added dropwise followed by the addition of more triethylamine (3.9 mL, 28 mmol). The mixture was stirred at room temperature overnight, then concentrated in vacuo. 1 L of toluene was added, the mixture was cooled to 0° C., then 125 mL of HCl (13% aqueous solution) was added. The ice bath was removed, the mixture was stirred for 30 minutes, then the layers were separated and the organics washed with water and evaporated to dryness. The residue was purified by silica gel chromatography (Hexanes/EtOAc=3:1) to afford 21.8 g of ethyl 3-(5-chloro-2-cyclopropoxyphenyl)-3-oxopropanoate. LCMS (ESI) m+H=283.0; 1H NMR (400 MHz, CDCl3) δ: 7.81 (t, 1H), 7.44 (dd, 1H), 7.29 (d, 1H), 4.24 (m, 2H), 3.87 (s, 2H), 3.78 (m, 1H), 1.23 (t, 2H), 0.85 (m, 4H).
Reaction SMILES: [CH2:1]=[CH2:2].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](Cl)=[O:12])=[CH:6][CH:5]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Br:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[CH2:10][C:11](=[O:12])[CH2:2][CH2:1]2
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: C=C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2cc(Br)ccc2C1
Temperature: -10 °C

Procedure:
To a two-liter round bottom flask equipped with a gas inlet tube connected to an external tank of ethylene, an addition funnel containing a solution of the crude 4-bromophenylacetyl chloride described above in methylene chloride (75 ml), a thermometer, a gas inlet adapter connected to a bubbler and a positive nitrogen flow, and a heavy-duty magnetic stirrer was added dry methylene chloride (1000 ml) and aluminium chloride (56 g, 0.42 mole). The stirred suspension was cooled to -10° C. using an ice/salt bath, and ethylene was introduced through the gas inlet tube, which was positioned just above the vortex. Dropwise addition of the phenylacetyl chloride solution was started at a moderate rate, and adjusted periodically so that the reaction temperature stayed below 0° C. Ethylene flow was continued for 30 minutes after addition of the acid chloride solution was complete, and then reaction mixture was poured over 2000 ml of ice, stirred vigorously for a few minutes, and left to sit until the ice melted. The methylene chloride layer was separated and the aqueous layer was extracted three times with methylene chloride (100 ml each). Combined methylene chloride layers were filtered through a short silica gel plug and then evaporated under reduced pressure to leave an amber-colored oil, which was purified using silica gel column chromatography, eluting with ethyl acetate:hexane (35:65) to give 6-bromo-2-tetralone as an amber crystalline solid. (25 g, 95%).