Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:13])[CH:4]=1.[OH:14]C1C2C(=CC=CC=2)N=C(C)C=1.ClC1C=CC=C(C(OO)=O)C=1.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[N+:6]([O-:14])=[C:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2
Reactant: Cc1cc(O)c2ccccc2n1
Reactant: COc1cc(C)nc2ccccc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(C)[n+]([O-])c2ccccc12
Temperature: 40 °C

Procedure:
31 g of 4-methoxyquinaldine (prepared from 4-hydroxyquinaldine by the method of M. Maurin, A. Ch. 4 [11] (1935), 301 and 335) are taken up in 80 ml of chloroform at room temperature, and 42 g of 85% strength m-chloroperbenzoic acid are added a little at a time, with stirring. The mixture is heated at 40° C. for 2 hours and is then cooled to 20° C. and brought to pH 6-7 with about 9 g of NaOH in 50 ml of H2O. The organic phase is separated off, dried with Na2SO4, filtered and concentrated. 34 g of crude product remain, and are recrystallized from toluene with addition of a small amount of solid KOH. 12 g of pure 4-methoxyquinaldine-N-oxide are obtained. Melting point 131°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:48][CH2:47][CH2:46][C:40]3([CH2:44][NH:43][C:42](=[O:45])[CH2:41]3)[CH2:39]2)[C:34]([F:49])=[CH:33][N:32]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:48][CH2:47][CH2:46][C:40]5([CH2:44][NH:43][C:42](=[O:45])[CH2:41]5)[CH2:39]4)[C:34]([F:49])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: O=C1CC2(CCC[C@H](Nc3nc(Cl)ncc3F)C2)CN1
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: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC5(CNC(=O)C5)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 120 °C
Yield: 90.3 %

Procedure:
To a solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.083 g, 0.195 mmol) in acetonitrile (1.6 mL) was added (7S)-7-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-azaspiro[4.5]decan-3-one (62c) (0.053 g, 0.177 mmol) and degassed under N2. Aqueous Na2CO3 (0.266 mL of 2 M solution, 0.5320 mmol) was added followed by Pd(PPh3)4 (0.031 g, 0.027 mmol). The reaction was sealed and heated in a microwave at 120° C. for 30 min then concentrated in vacuo. The material was diluted in CH2Cl2 and silica gel chromatography using a gradient of Hexanes:EtOAc then 20% MeOH in CH2Cl2. Pure fractions were combined and concentrated to give 91 mg of 62d. LCMS+: 569.26 at 4.20 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:26](OC4C=CC([N+]([O-])=O)=CC=4)=[O:27])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.Cl.[NH2:39][CH:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[NH2:39][CH:40]1[CH2:44][CH2:43][N:42]([C:26]([N:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=3)[CH2:14][CH:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:8]=3)[CH2:10]2)=[O:27])[CH2:41]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Reactant: NC1CCNC1
Agent: Cl
Product: NC1CCN(C(=O)N2CC(c3ccc(OC(F)(F)F)cc3)CC(c3nc(C4CC4)no3)C2)C1

Procedure:
90 mg (0.17 mmol) of the compound from Example 176A and 83 mg (0.52 mmol) of 3-aminopyrrolidine hydrochloride were reacted according to the General Method 6. Yield: 13 mg (15% of theory)
Reaction SMILES: [Cl:1][C:2]1[C:20]([F:21])=[C:19]([Cl:22])[CH:18]=[C:17]([F:23])[C:3]=1[C:4]([CH:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]>O>[Cl:1][C:2]1[C:20]([F:21])=[C:19]([Cl:22])[CH:18]=[C:17]([F:23])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Solvent: O
Product: CCOC(=O)CC(=O)c1c(F)cc(Cl)c(F)c1Cl
Yield: 49.8 %

Procedure:
0.04 g of p-toluenetoluenesulphonic acid is added to an emulsion of 34.7 g of crude diethyl (2,4-dichloro-3,6-difluorobenzoyl)-malonate in 40 ml of water. The mixture is heated at the boiling point for 3 hours, while stirring thoroughly, the cooled emulsion is extracted several times with methylene chloride, the combined CH2Cl2 solutions are washed once with saturated sodium chloride solution and dried with Na2SO4 and the solvent is distilled off in vacuo. Fractionation of the residue (33.9 g) in vacuo gives 13.9 g of ethyl (2,4-dichloro-3,6-difluorobenzoyl)-acetate of boiling point 110°-115° C./0.05 mbar, nD25 : 1.5241.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[F:7][C:8]([F:24])([F:23])[C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[C:12]([CH2:14][C:15](OCC)=[O:16])=O>>[OH:16][C:15]1[N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[N:1]=[C:12]([C:11]2[CH:10]=[C:9]([C:8]([F:7])([F:23])[F:24])[CH:22]=[CH:21][CH:20]=2)[CH:14]=1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)c1cccc(C(F)(F)F)c1
Product: Oc1cc(-c2cccc(C(F)(F)F)c2)nc2ccnn12

Procedure:
A mixture of 0.83 g. of 3-aminopyrazole and 2.61 g. of ethyl m-trifluoromethylbenzoylacetate is heated on a steam bath for 2 hours. After cooling the desired compound is collected by filtration, m.p. 305°-310° C.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[CH:6]=[C:7]([CH:9]=[O:10])[S:8][C:4]=2[CH:3]=1.[CH2:13]([B-](F)(F)F)[CH2:14][CH2:15][CH3:16].[K+]>>[CH2:13]([C:2]1[CH:12]=[CH:11][C:5]2[CH:6]=[C:7]([CH:9]=[O:10])[S:8][C:4]=2[CH:3]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=Cc1cc2ccc(Br)cc2s1
Reactant: CCCC[B-](F)(F)F
Agent: [K+]
Product: CCCCc1ccc2cc(C=O)sc2c1
Yield: 85.6 %

Procedure:
The compound was synthesized as in Example 3.1 using 6-bromobenzothiophene-2-carbaldehyde (110 mg, 0.46 mmol) in place of 5-bromo-2-formylfuran and potassium butyltrifluoroborate (113 mg, 0.69 mmol) in place of hexylboronic acid to give 6-butylbenzothiophene-2-carbaldehyde (86 mg, 78%). Used without further characterization.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1.Cl.Cl.[CH3:41][N:42]([CH3:47])[CH:43]1[CH2:46][NH:45][CH2:44]1.CN(C)C1CNC1>CC(N(C)C)=O>[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([N:45]3[CH2:46][CH:43]([N:42]([CH3:47])[CH3:41])[CH2:44]3)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1
Reactant: CN(C)C1CNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
DIPEA (0.341 mL, 1.96 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 20, 254 mg, 0.61 mmol) and N,N-dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 106 mg, 0.61 mmol) in DMA (4 mL) and the mixture was heated to 100° C. for 0.5 h. Further N,N-dimethylazetidin-3-amine (35 mg, 0.19 mmol) was then added and the mixture was heated at 100° C. for a further 2 h and was then left at r.t. overnight. The mixture was purified directly by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and was concentrated in vacuo onto silica. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (310 mg, 102%) as an orange solid, which was used without further purification; 1H NMR: 2.14 (6H, s), 3.08-3.18 (1H, m), 3.76 (2H, dd), 3.89 (3H, s), 4.02-4.11 (2H, m), 6.28 (1H, s), 7.12 (1H, td), 7.30-7.39 (1H, m), 8.12 (1H, s), 8.37 (1H, br s), 8.42 (1H, s), 8.68 (1H, s), 8.83 (1H, d), 8.94 (1H, d); m/z: ES+ MH+ 495.56.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:15][CH3:16])=[CH:6][C:7]([O:13][CH3:14])=[C:8]([CH:12]=1)[C:9]([OH:11])=O)([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[Br:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[CH2:37][NH:36][CH2:35]2>CN(C=O)C>[Br:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[CH2:37][N:36]([C:9]([C:8]1[CH:12]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]([O:15][CH3:16])=[CH:6][C:7]=1[O:13][CH3:14])=[O:11])[CH2:35]2
Reactant: COc1cc(OC)c(C(C)C)cc1C(=O)O
Reactant: Brc1ccc2c(c1)CNC2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc(OC)c(C(C)C)cc1C(=O)N1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a mixture of 5-isopropyl-2,4-dimethoxybenzoic acid (2.45 g, 10.9 mmol), HOBt (1.61 g, 11.9 mmol) and EDC (1.85 g, 11.9 mmol) in anhydrous DMF (33 ml) under N2 was added 5-bromo-2,3-dihydro-1H-isoindole (1.97 g, 9.95 mmol) and stirred at room temperature overnight. The reaction was quenched by diluting with NaOH (1M, aq.) and extracting the product with EtOAc (×2). The combined organic layers were washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness to leave a brown oil. The product was purified by flash column chromatography using gradient elution (ether/petrol) to yield (5-bromo-1,3-dihydro-isoindol-2-yl)-(5-isopropyl-2,4-dimethoxyphenyl)-methanone as a beige solid (3 g). 1H NMR (Me-d3-OD) 7.60-7.13 (3H, m), 7.14 (1H, s), 6.71 (1H, s), 4.89 (2H, d), 4.64 (2H, d), 3.93 (3H, s), 3.90 (3H, s), 3.27 (1H, sept), 1.20 (6H, d). MS: [M+H]+ 404/406.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[OH-].[K+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: OCc1ccncc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Product: O=[N+]([O-])c1ccc(OCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-hydroxymethyl-pyridine (2.23 g, 20 mmol) is added to a suspension of KOH (1.32 g, 20 mmol) and Aliquat 336 (0.937 mL). After stirring for 5 min at rt, 1-chloro-4-nitro-benzene (2.68 g, 16.7 mmol) is added. The resulting reaction mixture is further stirred at rt for 5 min and then at 80° C. for 2 h. The reaction mixture is filtered over silica gel (15 g), concentrated under reduced pressure, and flash chronatographed (silica gel, 3×50 cm, acetone/CH2Cl2=5:95→15:85) to give the title compound as a yellow solid: M+H=231.0; 1H-NMR (400 MHz, DMSO-d6): 8.58 (d, 6.5 Hz, 2H, pyrimidinyl), 8.22 (d, 8.5 Hz, 2H, phenyl-NO2), 7.44 (d, 6.5 Hz, pyrimidinyl), 7.21 (d, 8.5 Hz, 2H, phenyl-NO2), 5.34 (s, 2H, CH2); Rf (acetone/CH2Cl2=15:85): 0.32; HPLC (System 1): 3.40 min.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([C:21]1[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=1)#[CH:20].C(N(CC)CC)C>O1CCCC1>[C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:20]=[C:19]([C:21]4[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(Nc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(Nc4ccccc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 81.6 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-phenylamino-phenyl)-acetohydroximoyl chloride (150 mg, 0.576 mmol) described in Manufacturing Example 69-1-4 and 3-ethynyl-pyridin-2,6-diamine (48.9 mg, 0.367 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (201 μL, 1.44 mmol). This mixture was stirred for 6.5 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (107 mg, 52%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2].C(N(CC)CC)C.[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH:15][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:31][CH:32]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)Nc2ccccc2N)c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C#N)c2)cc1
Reaction time: 20 h
Yield: 87.5 %

Procedure:
To a solution of N1-(3-cyanobenzoyl)-1,2-benzenediamine (500 mg, 2.1 mmol), triethylamine (0.44 mL, 3.2 mmol) in methylene chloride (100 mL) was added 4-tert-butylbenzoyl chloride (0.41 mL, 2.1 mmol). After stirring for 20 hours, the reaction mixture was concentrated in vacuo. Chromatography (silica gel, 20% ethyl acetate/80% hexanes) yielded 730 mg (87%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:21][C:22]([OH:24])=[O:23])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:11]=3)[CH3:2].Br[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28](=[O:29])[O:27]1>C1COCC1>[O:29]=[C:28]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]([O:23][C:22](=[O:24])[CH2:21][C:3]2([CH2:1][CH3:2])[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH2:5][O:4]2)=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:18])([F:20])[F:19])[CH:11]=4)[O:27]1
Reactant: CCC1(CC(=O)O)OCCc2c1[nH]c1cc(OC(F)(F)F)ccc21
Reactant: O=C1OC(Br)c2ccccc21
Solvent: C1CCOC1
Product: CCC1(CC(=O)OC2OC(=O)c3ccccc32)OCCc2c1[nH]c1cc(OC(F)(F)F)ccc21
Yield: 74.6 %

Procedure:
A solution of 1-ethyl-1,3,4,9-tetrahydro-7-(trifluoromethoxy)pyrano[3,4-b]indole-1-acetic acid (0.650 g, 1.89 mmol, prepared according to the procedure of Example 1), 3-bromophthalid (0.402 g, 1.89 mmol) and TEA (0.382 g, 3.79 mmol) in dry THF (60 mL) was refluxed for 4 hours. The solvent was evaporated and the residue was partitioned between water and ether. The extracts were washed with 5% NaHCO3 and brine, dried (MgSO4) and evaporated to dryness. Flash chromatography of the residue (on silica Merck-60, eluant: CHCl3) provided 0.670 g (74.6%) of the pure product (as a mixture of diastereomers) which was recrystallized from ether-hexane, m.p. 150° C. (softening starts at 124° C.).
Reaction SMILES: [ClH:1].[CH:2]1([C:8]2([C:14]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>[Pd].C(O)C>[ClH:1].[CH:2]1([C:8]2([C:14]([O:16][CH:17]3[CH2:22][NH:21][C:20]([CH3:23])=[N:19][CH2:18]3)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1ncc(OC(=O)C2(C3CCCCC3)CCCCC2)cn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1=NCC(OC(=O)C2(C3CCCCC3)CCCCC2)CN1

Procedure:
A mixture of 2-methylpyrimidin-5-yl 1-cyclohexylcyclohexane1-carboxylate hydrochloride and 10% palladium on carbon (0.12 g) in ethanol (10 ml) was hydrogenated at room pressure. After the hydrogen absorption had ceased, the catalyst was filtered off and the solvent was evaporated in vacuo. The residue was purified by column chromatography (methylene chloride/methanol/water 80:20:2) to give 0.43 g of 2-methyl-1,4,5,6-tetrahydropyrimidin 5-yl 1-cyclohexylcyclohexane-1-carboxylate hydrochloride. M.p. 212°-214° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Cl.[CH3:21][C:22]1([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:24]3[CH2:25][C:22]([CH3:21])([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:23]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CC1(NC(=O)C(F)(F)F)CNC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(C)(NC(=O)C(F)(F)F)C3)c(F)c21
Yield: 37.5 %

Procedure:
A solution of 1.1 g (4 mmoles) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.32 g (6 mmoles) of 3-methyl-3-trifluoroacetamidoazetidine hydrochloride and 0.8 g (8 mmoles) of triethylamine in 10 ml of pyridine is heated under reflux for 3 hours. Cooling, filtering and washing with water acidified with a little acetic acid yields 0.65 g (37%) of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-methyl-3-trifluoroacetamido-1-azetidinyl)-3-quinolinecarboxylic acid, melting at 196°-210° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].CCO>[Fe].O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CCN(c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccc2[N+](=O)[O-])CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC1CCN(c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccc2N)CC1
Temperature: 80 °C
Yield: 53.8 %

Procedure:
A flask charged with 4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.080 g, 0.20 mmol) (as prepared in the previous step), ammonium chloride (0.10 g, 2.0 mmol), iron powder (0.055 g, 10 mmol), EtOH (1 mL) and water (0.5 mL) was heated at 80° C. for 30 min. The reaction was filtered though Celite, concentrated and eluted from a 10-g SPE cartridge (silica) with 20% EtOAc/hexane to give 0.040 g (50%) of the title compound as a yellow oil. 1H-NMR (400 MHz, CDCl3): δ 7.08 (d, 1H), 6.97 (dd, 1H), 6.72 (d, 1H), 5.89 (m, 1H), 4.75 (br s, 2H), 4.08 (m, 2H), 3.63 (m, 2H), 3.12 (m, 2H), 2.62 (m, 2H), 2.50 (m, 2H), 1.78 (m, 2H), 1.52 (s, 9H), 1.38 (m, 3H), 1.00 (d, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]([NH:21][NH2:22])=[O:20])[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[C:25]([O:28][CH2:29][C:30](Cl)=[O:31])(=[O:27])[CH3:26]>>[C:25]([O:28][CH2:29][C:30](=[O:31])[NH:22][NH:21][C:19]([C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:23])([F:1])[F:24])[CH:5]=3)[C:14]=2[CH:15]=1)=[O:20])(=[O:27])[CH3:26]
Reactant: NNC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1
Reactant: CC(=O)OCC(=O)Cl
Product: CC(=O)OCC(=O)NNC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1
Yield: 94 %

Procedure:
In the same manner as in Reference Example 61 and using 3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-carbohydrazide instead of ethyl 2-aminoisonicotinate and acetoxyacetyl chloride instead of 3-phenylpropanoyl chloride, the title compound (yield 94%) was obtained as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][NH2:16])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH2:15][NH:16][S:33]([CH3:32])(=[O:35])=[O:34])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CN
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.5 %

Procedure:
To a solution of 6-nitro-2,2-dimethyl-3-aminomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.43 g, 1.31 mmol) and triethylamine (0.22 ml, 1.58 mmol) in dichloromethane (15 ml) was added methanesulfonylchloride (0.12 ml, 1.55 mol). The solution was stirred at room temperature for four hours, and then water was added. The organic phase was separated and evaporated under reduced pressure. The residue was washed with diethyl ether, affording 0.3 g of 6-nitro-2,2-dimethyl-3-(methanesulfonamido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 195° C.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].ClCCCl.[F:17][C:18]([F:30])([F:29])[C:19]1[CH:20]=[C:21]([CH2:25][C:26](Cl)=[O:27])[CH:22]=[CH:23][CH:24]=1>O>[F:17][C:18]([F:29])([F:30])[C:19]1[CH:20]=[C:21]([CH2:25][C:26]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: COc1ccc(C(=O)Cc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Anisole (32.4 g) and aluminium trichloride (36.0 g) are added to 1,2-dichloroethane (240 ml). The mixture is cooled to -5° and (3-trifluoromethylphenyl)-acetyl chloride (66.8 g) is slowly added. The mixture is stirred for 11/2 hours and poured into a mixture of crushed ice (400 g) and water (150 ml). After heating to room temperature, the compound is extracted with ether (3×200 ml). The combined organic phases are washed with a 2% aqueous solution of sodium hydroxide (200 ml and with water (3×200 ml), dried over magnesium sulphate and the solvents are removed invacuo. The residue is recrystallised from hexane. The product is dried in vacuo to constant weight to yield 2-(3-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethanone, m.p. 94°-95°.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:15]=[C:14]([CH3:16])[O:13][N:12]=2)[S:9][CH:10]=1)=[O:5])C.O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:16][C:14]1[O:13][N:12]=[C:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH:15]=1
Reactant: CCOC(=O)c1csc(-c2cc(C)on2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2nc(C(=O)O)cs2)no1
Temperature: 25 °C
Reaction time: 15 h
Yield: 10 %

Procedure:
A mixture of 2-(5-methyl-isoxazol-3-yl)-thiazole-4-carboxylic acid ethyl ester (0.24 g, 1.0 mmol) and lithium hydroxide monohydrate (84 mg, 2.0 mmol) was dissolved in THF/H2O (2/1, 9 mL). The resulting reaction was allowed to stir at room temperature for about 15 hours, then acidified using 20% aqueous HCl. The solvent was removed by lyophilization to provide 2-(5-methyl-isoxazol-3-yl)-thiazole-4-carboxylic acid (21 mg).