Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:24]3[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]3)[CH:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(Nc1cc(F)ccc1[N+](=O)[O-])c1cccc(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])c1cccc(Cl)c1
Yield: 11.4 %

Procedure:
N-(1-(3-Chlorophenyl)ethyl)-5-fluoro-2-nitrobenzenamine (522 mg, 1.8 mmol), t-butyl piperazine-1-carboxylate (329 mg, 1.8 mmol), N,N-diisopropylethylamine (457 mg, 3.5 mmol) were stirred at 90° C. in dry acetonitrile (50 mL) for 24 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (95 mg, 12% yield). 1H NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 8.06 (d, 1H), 7.33-7.21 (m, 4H), 6.15 (d, 1H), 5.58 (s, 1H), 4.53 (m, 1H), 3.43 (m, 4H), 3.21 (m, 2H), 3.13 (m, 2H), 1.63 (d, 3H), 1.46 (s, 9H); MS (ESI) m/z: Calculated for C23H29ClN4O4: 460.19; Observed: 483.3 (M++Na).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:23]([O:26][C:27](Cl)=[O:28])([CH3:25])[CH3:24]>O>[CH:23]([O:26][C:27]([NH:1][C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1)=[O:28])([CH3:25])[CH3:24]
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1ccc2nc(-c3ccccc3)oc2n1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1ccc2nc(-c3ccccc3)oc2n1
Reaction time: 120 h

Procedure:
A mixture of 300 mg. of 5-amino-2-phenyloxazolo[ 5,4-b]pyridine and 3 ml. of pyridine was cooled in ice and to it was added 0.2 ml. of isopropylchloroformate. The mixture was allowed to age in the refrigerator for 5 days, and diluted with ice and water. The precipitate was collected and recrystallized from isopropanol to give 5-isopropoxycarbonylamino-2-phenyloxazolo[ 5,4-b]pyridine, m.p. 210°-211° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][C@@H:13]2[CH2:15][C@H:10]1[CH2:11][N:12]2[CH3:16])[NH2:5].C(OC(N[C:25](=[N:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:26]1C=CC=N1)=O)(C)(C)C>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([N:5]=[C:25]([NH2:26])[N:31]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][C@@H:13]2[CH2:15][C@H:10]1[CH2:11][N:12]2[CH3:16]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: Cc1cc(N)ccc1N1C[C@@H]2C[C@H]1CN2C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N=C(N)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1N1C[C@@H]2C[C@H]1CN2C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Compound (Da), 3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]aniline, (0.105 g, 0.6 mmol) and 1-(tert-butoxycarbonylamino(tert-butoxycarbonylimino)methyl)pyrazole (H) (0.186 g, 0.6 mmol) were combined in DMF (2 mL) and stirred at ambient temperature for 3 days. The reaction was monitored by LCMS. The homogenous reaction mixture was then diluted with water (20 mL), the solid precipitate formed was isolated by filtration, and purified by column chromatography (silica gel, CH2Cl2 then 2-5% MeOH in CH2Cl2) to give [3-methyl-4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl)phenyl][N,N-bis(tert-butoxycarbonyl)]guanidine; LCMS: purity: 99%; MS (m/e): 460 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([NH2:8])=[NH:7].[Cl:14][C:15]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:16]=1[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20]>>[NH2:22][CH2:21][C:18]1[C:19]([NH2:20])=[N:7][C:6]([C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:8][C:17]=1[C:16]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:15]=1[Cl:14]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: COc1ccc(C(=N)N)cc1OC
Product: COc1ccc(-c2nc(N)c(CN)c(-c3ccc(Cl)cc3Cl)n2)cc1OC

Procedure:
The title compound, MS: m/e=405.3 (M+H+), was prepared from 3,4-dimethoxy-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH:38]([CH3:40])[CH3:39])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH:38]([NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])([CH3:40])[CH3:39]
Reactant: CC(C)NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-isopropyl-benzenesulfonamide [CAS 118837-66-4] according to general procedure II. Yellow solid. MS (ISP) 570.2 [(M−H)−]; mp 222° C.
Reaction SMILES: [CH:1]([OH:3])=O.[CH:4]1([O:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]=[C:12](OC(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1>C(OCC)(=O)C>[CH:4]1([O:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]=[C:12]([CH2:1][OH:3])[CH:11]=2)[CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=CO
Reactant: COc1cnc(OC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1OC1CCCC1
Solvent: CCOC(C)=O
Product: COc1cnc(CO)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
90% Formic acid (5.5 mL) is added to a suspension of 4-cyclopentyloxy-5-methoxy-2-trityloxypyridine (1.2 g) in ethyl acetate (8.5 mL) and the mixture stirred at room temperature for 1 hours. The mixture is diluted with ethyl acetate and washed with brine then aqueous sodium bicarbonate until the washings are neutral. The brine washings are neutralised with solid sodium bicarbonate and extracted with ethyl acetate. After drying (MgSO4) the extracts are evaporated to give 4-cyclopentyloxy-2-hydroxymethyl-5-methoxypyridine (360 mg) as a white solid, m.p. 93-94.5° C. [Elemental analysis: —C, 64.7; H, 7.80; N, 6.11%. calculated: —C, 64.55; H, 7.68; N, 6.27%.].
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:3]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:33]=1[CH2:34]Br>C1COCC1>[F:40][C:38]1[CH:37]=[CH:36][C:33]([CH2:34][C@H:3]2[C:2](=[O:1])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4]2)=[C:32]([CH3:31])[CH:39]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Cc1cc(F)ccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C[C@@H]1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 0 %

Procedure:
Step (c) (S)-Di-tert-butyl 5-oxopyrrolidine-1,2-dicarboxylate (1.15 g, 4.0 mmol) was dissolved in dry THF (20 mL) and the solution was cooled to −78° C. A solution of LiHMDS (1M in hexanes, 4.4 mL, 4.4 mmol) then was added dropwise under nitrogen. The mixture was cooled at −78° C. for 40 minutes and then a solution of 2-methyl-4-fluorobenzyl bromide (975 mg, 4.8 mmol) in THF (5 mL) was added slowly. The mixture was stirred at −78° C. for 2 hours and then quenched with saturated ammonium chloride (20 mL). The mixture was extracted with diethyl ether (3×70 mL) and the combined extract was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Product was purified from the residue by flash column (eluted with a 4:1 hexanes/diethyl ether mixture) to give (2S,4R)-di-tert-butyl 4-(4-fluoro-2-methylbenzyl)-5-oxopyrrolidine-1,2-dicarboxylate (810 mg, 2.0 nmol, 49.7%), clean as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([O:13][CH2:14][C:15]4([CH2:17][CH2:16]4)[N:8]3[CH:7]=[C:6]([C:18]([O:20]CC)=[O:19])[C:5]2=[O:23])[C:11]=1[F:12].C([O-])([O-])=O.[K+].[K+]>CCO.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([O:13][CH2:14][C:15]4([CH2:17][CH2:16]4)[N:8]3[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:23])[C:11]=1[F:12]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC21CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC21CC1

Procedure:
To a solution of ethyl 9,10-difluoro-7-oxo-2,7-dihydrospiro[[1,4]oxazino[2,3,4-ij]quinoline-3,1′-cyclopropane]-6-carboxylate (1.3 g, 4 mmol) in EtOH/water (50:50 v/v, 55 mL) was added K2CO3 powder (1.65 g, 12 mmol) and the mixture was heated under reflux for 2 h. The solvent was removed to dryness. The remaining solid was acidified to pH6 by using 2N acetic acid. A precipitate formed and was collected by filtration, washed with water and then dried to give the title compound (0.656 g, 2.24 mmol as a light yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.29 (2H, t), 1.8 (2H, t), 4.56 (2H, s), 7.84 (1H, m), 8.51 (1H, s), 14.3 (1H, b). MS (EP) m/z: 294 (M++1). (Calcd for C14H9F2NO4, 293.22)
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C@:17]3([C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@H:20]([C:30]([OH:32])=O)[NH:19][C@H:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>>[C:64]1([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccccc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Yield: 23.5 %

Procedure:
In a manner similar to the method described in Example 5, chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 136 (0.15 g, 0.26 mmol), was reacted with diisopropylethylamine (0.17 g, 1.3 mmol), diphenylphosphinic chloride (0.17 g, 0.53 mmol), then reacted with aniline (Aldrich) (0.05 g, 0.53 mmol) to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid phenylamide as a white foam (Yield 0.033 g, 24%).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([F:24])[F:23])=[C:16]([CH3:25])[CH:15]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[F:23][CH:22]([F:24])[CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])[C:7]=3[CH2:8]2)[CH3:13])=[CH:15][C:16]=1[CH3:25]
Reactant: O=COc1ccccc1
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ccc1OCC(F)F
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)ccc1OCC(F)F
Yield: 49 %

Procedure:
The title compound is prepared in 49% yield (60 mg, yellow oil) from 4-chloro-2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.27 mmol, Intermediate-28, single enantiomer) and phenyl formate (67 mg, 0.61 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([NH:10][CH2:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:20]=[C:21]3[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=2)[NH:24][CH:23]=[C:22]3[CH:31]2[CH2:36][CH2:35][N:34]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH2:33][CH2:32]2)[CH:15]=[CH:16][C:17]=1[F:18])[CH3:9].[CH2:42](N)[CH3:43]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([NH:10][CH2:11][C:12]2[CH:13]=[C:14]([C:19]3[CH:20]=[C:21]4[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=3)[NH:24][CH:23]=[C:22]4[CH:31]3[CH2:32][CH2:33][N:34]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH2:35][CH2:36]3)[CH:15]=[CH:16][C:17]=2[F:18])[CH2:43][CH2:42][CH2:9]1
Reactant: CCN
Reactant: CCNCc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)ccc1F
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(F)c(CNC5CCC5)c4)cc23)CC1
Yield: 42 %

Procedure:
The title compound was prepared according to the general procedure of 5-{3-[(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting cyclobutanamine (39 mg, 0.46 mmol) for ethylamine to afford 20 mg of the title compound (42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH:7]=[CH:6]2.C1C(=O)N([Br:21])C(=O)C1>C(#N)C>[Br:21][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9](=[O:13])[NH:8][CH:7]=1
Reactant: COc1ccc2c(=O)[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc2c(=O)[nH]cc(Br)c2c1
Reaction time: 2 h
Yield: 55.2 %

Procedure:
To a solution of 6-methoxyisoquinolin-1(2H)-one (2.5 g, 14.27 mmol) in acetonitrile (10 ml) was added NBS (2.54 g, 14.27 mmol) at room temperature under argon atmosphere. The reaction mass was stirred at the same temperature for 2 h. The precipitated solid was filtered to get crude compound (2 g, 55.2%). The crude compound was taken to the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.41 (s, 1H), 8.17-8.15 (d, J=8 Hz, 1H), 7.53 (s, 1H), 7.19-7.11 (m, 2H), 3.93 (s, 3H); MS: MS m/z 256.06 (M++2).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-])=O)=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18].O.NN>CO.[Ni]>[NH2:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:19])[C:6](=[O:18])[CH2:7][CH2:8]2
Reactant: CN(C)CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CN(C)CCN1C(=O)CCc2cc(N)ccc21
Temperature: 25 °C

Procedure:
A suspension of 1-(2-(dimethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (320 mg, 1.215 mmol) in dry methanol (10 mL) was treated with Ra—Ni (˜0.05 g) followed by hydrazine hydrate (0.38 mL, 12.2 mmol) at room temperature and the resulting mixture was refluxed for 20 min. The colorless reaction was cooled to room temperature, filtered through a celite pad, washed with methanol (2×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95). Yield: 280 mg of colorless oil (98%). 1H NMR (CDCl3) δ: 6.86 (d, J=8.4 Hz, 1H), 6.57 (dd, J=2.7, 8.4 Hz, 1H), 6.51 (d, J=2.1 Hz, 1H), 4.01 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.2 Hz, 2H), 2.58 (t, J=7.2 Hz, 2H), 2.51 (t, J=7.2 Hz, 2H), 2.31 (s, 6H). MS (ESI): 234.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([OH:24])[CH:4]([NH:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20])[C:5](OCC)=[O:6].[CH3:27][NH2:28]>C(O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:10][CH:4]([C:5](=[O:6])[NH:28][CH3:27])[CH:3]([OH:24])[C:2]([F:26])([F:25])[F:1])=[O:23])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=1
Reactant: CN
Reactant: CCOC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(O)C(F)(F)F
Solvent: CCO
Product: CNC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.1 g (7.9 mmol) of ethyl 4,4,4-trifluoro-2-(4-fluoro-2-trifluoromethylbenzoylamino)-3-hydroxybutyrate were dissolved in ethanol. At RT, 20 ml of a 3.9% strength solution of methylamine in ethanol was added. After 5 h of stirring at RT, methylamine gas was introduced for 10 min and the mixture was stirred at RT for 16 h. The reaction solution was then concentrated, and the residue was washed with MTBE. This gave 1.8 g (61% of theory) of the title compound as colorless crystals (diastereomer ratio 3:1) of m.p. 212° C.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[N:12]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CC(O)C>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([N:15]3[CH2:16][CH2:17][CH2:18][N:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:14]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Fc1ccc2ncc(Br)n2n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc3ncc(Br)n3n2)CC1
Yield: 195.9 %

Procedure:
A stirred solution of 3-bromo-6-fluoroimidazo[1,2-b]pyridazine (1.6 g, 7.6 mmol), tert-butyl 1,4-diazepane-1-carboxylate [112275-50-0] (4.4 mL, 22.6 mmol), and Hunig's base [7087-68-5] (5.3 mL, 30.4 mmol) in 2-propanol (25 mL) was heated to 65° C. for 3d then partitioned between brine and ethyl acetate. The extract was dried (CaSO4) and evaporated to provide 5.9 g of clear orange liquid which was flash chromatographed (silica gel eluted with 10% (v/v) methanol/ethyl acetate) and crystallized from ethyl acetate/heptane to afford 2.0 g of white powder, mp. 101-102° C. 1H NMR (400 MHz, DMSO-d6) δ ppm (rotomers present) 1.03 (s, 5H) 1.17 (s, 4H) 1.73 (br. s., 1H) 1.85 (br. s., 1H) 2.43-2.47 (m, 1H) 3.20-3.29 (m, 3H) 3.49 (d, J=5.51 Hz, 1H) 3.55-3.66 (m, 3H) 3.70-3.79 (m, 2H) 7.05 (d, J=9.92 Hz, 1H) 7.49 (d, J=7.28 Hz, 1H) 7.78 (d, J=9.70 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm (rotomers present) 24.50, 24.83, 27.45, 27.61, 44.10, 44.78, 44.83, 45.33, 47.58, 47.74, 48.01, 48.09, 78.11, 78.27, 98.80, 109.23, 109.61, 125.65, 125.77, 130.81, 130.89, 136.07, 153.01, 153.18, 153.90, 154.19. LRMS (ESI) m/z 396.1/398.1 [(M+H)]+, calc'd for C16H22BrN5O2: 396.29.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[O:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29].Cl>CN(C)C=O.O>[CH3:29][C:28]1[O:27][C:26]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:25][C:24]=1[CH2:23][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[O:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(CCCCCc2ccc(O)cc2)O1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCCCC2OC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.9 %

Procedure:
To a solution of 5-[5-(4-hydroxyphenyl)pentyl]-2,4-oxazolidinedione (0.9 g) in N,N-dimethylformamide (DMF) (40 ml) was added sodium hydride (60% in oil, 0.28 g). The mixture was stirred for 15 minutes at room temperature, to which was then added 4-chloromethyl-5-methyl-2-phenyloxazole (0.85 g), and the mixture was stirred for 2 hours at 70° C. The reaction mixture was poured into water, acidified with 2N HCl, and subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then the solvent was distilled off. The oily residue was subjected to a silica gel column chromatography. From the fractions eluted with ethyl acetate--chloroform (1:5, v/v) was obtained 5-[5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]pentyl]-2,4-oxazolidinedione (0.86 g, 58%). Recrystallization from dichloromethane--isopropyl ether gave colorless prisms, m.p.120°-121° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:13])=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][C:6]=1[CH3:7].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:11]([O:10][C:8]([C:4]1[NH:5][C:6]([CH3:7])=[C:2]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([F:26])([F:25])[F:14])[C:3]=1[CH3:13])=[O:9])[CH3:12]
Reactant: CCOC(=O)c1[nH]c(C)c(Br)c1C
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1[nH]c(C)c(-c2ccccc2C(F)(F)F)c1C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
To a solution of ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (3.42 g, 20 mmol) in carbon tetrachloride (40 mL) was added a solution of bromine in carbon tetrachloride (10 mL) dropwise at 20° C. After the addition was complete, stirring was continued for 2 h. The reaction mixture was diluted with DCM, washed with aqueous NaHCO3 and water, and then dried over Na2SO4. Evaporation of solvent gave ethyl 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylate as a solid (4.8 g), which was used in the next step without purification. 1H-NMR (CDCl3): δ 9.36 (1H, s), 4.30 (2H, q), 228 (3H, s), 2.26 (3H, s), 1.36 (3H, t). To a solution of ethyl 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylate (2.4 g, 10 mmol) in DMF (25 mL) was added tetrakis(triphenylphosphine)palladium (2.3 g, 1 mmol). After stirring 15 min, the reaction mixture was charged with 2-(trifluoromethyl)-benzeneboronic acid (2.4 g, 12.5 mmol) and sodium carbonate (in 5 mL of water). The reaction mixture was heated to reflux overnight with stirring. After cooling, the reaction mixture was then diluted with water and extracted with DCM. The combined extracts were washed with water and dried over Na2SO4. Evaporation of solvent gave a crude material, which was purified by chromatography on silica gel column eluting with EtOAc-hexane (1:1) to give the title compound (1.5 g). MS (ES): 312 (MH+);
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][C:13]([OH:15])=O)[CH:8]=2)[O:3]1.[CH:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>C1COCC1>[CH3:16][C:2]1([CH3:1])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][C:13]([NH:27][CH:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH2:18]3)=[O:15])[CH:8]=2)[O:3]1
Reactant: CC1(C)C=Cc2cc(CC(=O)O)ccc2O1
Reactant: NC1CCCc2ccccc21
Solvent: C1CCOC1
Product: CC1(C)C=Cc2cc(CC(=O)NC3CCCc4ccccc43)ccc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9.6 g 1,1-carbonyldiimidazole (=CDl) dissolved in 85 ml THF was slowly added to a solution of 11.7 g of the 2,2-dimethyl-2H-chromen-6-yl acetic acid obtained above in 100 ml THF and stirred for 30 min. at room temperature. 8.8 ml 1,2,3,4-tetrahydro-1-naphthylamine, dissolved in 30 ml THF, was dropped slowly into this receiving solution, the resulting mixture was stirred for 1 hour and left to stand overnight at room temperature. The solvent was largely evaporated at reduced pressure, and the remaining residue was stirred with a mixture of diethyl ether and isopropanol (100:1 v/v) and crystallized. The resulting crystals were removed by suction and dried at 65° C. and 20 bar. Chromatography of the diethyl ether/isopropanol washing liquid on silica gel yielded further intermediate product, which was combined with the main quantity and dried. 17.5 g 2-(2,2-dimethyl-2H-chromen-6-yl)-N-1,2,3,4-tetrahydronaphth-1-yl acetamide was obtained as colorless solid, which was used without further purification for the subsequent reaction.