Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]([C:14]3[CH2:18][CH2:17][CH2:16][CH:15]=3)[CH:12]3[CH2:19][O:20][C:21]4[CH:22]=[C:23]([C:27]([O:29]C)=[O:28])[CH:24]=[CH:25][C:26]=4[C:11]3=[N:10]2)=[CH:5][C:4]=1[CH3:31])#[N:2].[OH-].[Na+]>CO.O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]([C:14]3[CH2:18][CH2:17][CH2:16][CH:15]=3)[CH:12]3[CH2:19][O:20][C:21]4[CH:22]=[C:23]([C:27]([OH:29])=[O:28])[CH:24]=[CH:25][C:26]=4[C:11]3=[N:10]2)=[CH:5][C:4]=1[CH3:31])#[N:2]
Reactant: COC(=O)c1ccc2c(c1)OCC1C2=NN(c2ccc(C#N)c(C)c2)C1C1=CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2C2=CCCC2)ccc1C#N
Temperature: 25 °C
Reaction time: 20 h
Yield: 55 %

Procedure:
To a solution of methyl 2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylate (125 mg, 0.30 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was added 1M aqueous sodium hydroxide (2 mL). The solution was stirred for 20 hours at ambient temperature. The resulting slurry was concentrated to half volume, acidified to pH=2 with 1M hydrochloric acid and collected by vacuum filtration (yellow solid, 66 mg, 55% yield). The title compound was largely present as (±)-(3RS,3aRS)-2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid. Reversed-phase HPLC on 4.6×50 mm C-18 column, tR=2.92 minutes (10 to 90% acetonitrile/water over 4 minutes at 4 mL/minute with detection 254 nm, at 20° C.); HRMS Calculated for C24H21N3O3: 400.1656 (M+H)+. Found: 400.1678. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61-1.87 (m, 2H), 2.03-2.13 (m, 2H), 2.17 (br. s., 2H), 2.39 (s, 3H), 3.83-3.91 (m, 1H), 3.97-4.06 (m, 1H), 4.65 (dd, J=10.20, 5.91 Hz, 1H), 5.44 (d, J=10.47 Hz, 1H), 5.60 (br. s., 1H), 6.86 (br. s., 1H), 7.11 (br. s., 1H), 7.42 (d, J=1.34 Hz, 1H), 7.53 (d, J=8.59 Hz, 1H), 7.56 (dd, J=8.19, 1.48 Hz, 1H), 7.90 (d, J=8.06 Hz, 1H), 13.12 (br. s., 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])(=[O:9])=[O:8])=[N:5][N:6]=1.C(Cl)(=O)[C:17](Cl)=[O:18]>C1(C)C(C)=CC=CC=1>[CH2:12]([CH:11]([NH:10][S:7]([C:4]1[S:3][C:2]([N:1]=[C:17]=[O:18])=[N:6][N:5]=1)(=[O:8])=[O:9])[CH2:14][CH3:15])[CH3:13]
Reactant: CCC(CC)NS(=O)(=O)c1nnc(N)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1C
Product: CCC(CC)NS(=O)(=O)c1nnc(N=C=O)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-5-[N-(1-ethylpropyl)aminosulfonyl]-1,3,4-thiadiazole (0.10 mole) and xylene (200 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. The mixture is dried by azeotroping off water and is then cooled to room temperature. Oxalyl chloride (0.15 mole) is added; the reaction mixture is warmed to a temperature of from 80° C. to about 100° C. and stirred at this temperature for a period of about 1 hour. The mixture is then heated to reflux and stirred for an additional 2 hours. Solvent is then stripped off leaving the desired product 5-[N-(1-ethylpropyl)aminosulfonyl]-1,3,4-thiadiazol-2-yl isocyanate dimer as the residue.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Br)C.C(OCC)C.[CH3:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[I:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)([OH:19])[CH3:17])=[CH:21][CH:22]=1
Reactant: CC(=O)c1ccc(I)cc1
Reactant: Ic1cccnc1
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)(c1ccc(I)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-iodopyridine (0.3 g, 1.463 mmol) in THF (4 ml) was added ethylmagnesium bromide in diethylether (3M) (0.976 ml, 2.93 mmol). The mixture was stirred at room temperature overnight. GC-MS after overnight showed no starting material and the reaction mixture was cooled in an ice-bath. 4-Iodoacetophenone (0.468 g, 1.902 mmol) was added. The ice-bath was removed after 15 minutes and the reaction was stirred at room temperature for 5 hrs. The reaction mixture was quenched with aqueous saturated NH4Cl solution before dilution with ethyl acetate. The organic phase was separated and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product which was purified by preparative HPLC (reversed phase). Fractions containing product were pooled and worked up (addition of NaHCO3, removal of acetonitrile followed by extraction with DCM) to obtain the title compound as yellowish oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.[OH:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:22]([NH:24][NH2:25])=[O:23].C(N(CC)CC)C.S([O-])(O)(=O)=O.[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:25][NH:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:19]([OH:18])[CH:20]=1
Reactant: COc1ccc(C(=O)NN)cc1O
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Temperature: 25 °C

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.18 g, 0.64 mmol) and 3-hydroxy-4-methoxy-benzoic acid hydrazide hydrochloride (0.18 g, 0.64 mmol) were coupled in N,N-dimethylformamide (5 mL) with triethylamine (0.30 mL) at 100° C. After cooling to room temperature and addition of 5% aqueous potassium hydrogen sulfate solution, the solid material is collected by Buchner filtration, washed with diethyl ether, water, and methanol, and then dried under house vacuum to give N′-[(Z)-(6-bromo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]-3-hydroxy-4-methoxybenzohydrazide as a tan powder.
Reaction SMILES: C[N:2]1[C:10](=O)[C:9]2[NH:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=3[O:19][CH3:20])=[N:6][C:5]=2[N:4](C)[C:3]1=[O:22].[OH-].[K+]>>[CH3:20][O:19][C:13]1[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]=1[C:7]1[N:8]=[C:9]2[C:5](=[N:4][C:3](=[O:22])[N:2]=[CH:10]2)[N:6]=1
Reactant: COc1cc(O)ccc1-c1nc2c([nH]1)c(=O)n(C)c(=O)n2C
Agent: [K+]
Agent: [OH-]
Product: COc1cc(O)ccc1C1=NC2=NC(=O)N=CC2=N1

Procedure:
1,3-dimethyl-8-(2-methoxy-4-hydroxy-phenyl)-1H,3H-purin-2,6-dione (hydrogenation in the presence of two equivalents of potassium hydroxide).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](O)=[O:31])=[CH:26][CH:25]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:30](=[O:31])[CH2:29][O:28][C:27]3[CH:33]=[CH:34][C:24]([F:23])=[CH:25][CH:26]=3)[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:9]=2[N:10]=1
Reactant: O=C(O)COc1ccc(F)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(F)cc3)CC2)c2nc(-c3cccnc3)sc2n1
Yield: 67 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-fluorophenoxyacetic acid in a yield of 67%, according to the procedure for the synthesis of example 50
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1.[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Agent: [Fe]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2nc(Cl)ccc2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-chloro-6-nitro-quinoline (12.5 g, 59.9 mmol) and ammonium chloridel (9.78 g, 183 mmol) were suspended in ethanol (175 mL) and water (50 mL). The resulting mixture was heated to 60° C. and iron powder (15.06 g, 270 mmol) was added as a solid in portions. The reaction mixture was stirred at 60° C. for 2 hours. LC-MS at this point showed one major peak corresponding to desired product. The reaction mixture was then concentrated to remove the majority of ethanol, and the residue was diluted with ethyl acetate and filtered to remove brown solids. The filter cake was washed with ethyl acetate. The filtrate was then dried over MgSO4, filtered and concentrated to afford a brown solid. This material was adsorbed onto silica and purified via Biotage automated flash column chromatography, eluting with 10-100% ethyl acetate/heptane. Relevant fractions were pooled and concentrated to afford a creamy yellow soft fluffy solid, which was dried under high vacuum to provide 6.45 g (60% yield) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[F:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([S:29][CH3:30])[N:24]=2)[CH:19]=[CH:18][C:17]=1[NH2:31]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:31][C:17]2[CH:18]=[CH:19][C:20]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([S:29][CH3:30])[N:24]=3)=[CH:21][C:16]=2[F:15])=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CSc1nccc(Oc2ccc(N)c(F)c2)n1
Solvent: C1CCOC1
Product: CSc1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)n1
Reaction time: 8 h
Yield: 40.4 %

Procedure:
A solution of 162 mg (0.732 mmol) 4-chloro-3-trifluoromethyl-phenyl isocyanate in 3 ml THF was added within 5 min. drop by drop at 0° C. to a solution of 184 mg (0.732 mmol) 2-fluoro-4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenylamine and stirring continued at r.t. overnight. The reaction mixture was evaporated and treated with 10 ml ether. Isolation of the precipitate gave 140 mg (40%) 1-(4-chloro-3-trifluoromethyl-phenyl)-3-[2-fluoro-4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenyl]-urea.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].[O:13]=[C:14]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[CH2:15][NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CS(C)=O>[O:13]=[C:14]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:28]=1)[CH2:15][NH:16][C:17](=[O:22])[C:18]([F:20])([F:21])[F:19]
Reactant: O=C(CNC(=O)C(F)(F)F)c1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1ccc(C(=O)CNC(=O)C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
1.06 g of sodium carbonate or 3.26 g of cesium carbonate were added to a stirred solution of 2.47 g of 4-(1-oxo-2-trifluoroacetamidoethyl)-phenol (1e) in 5 ml of dimethyl sulfoxide at room temperature and, after 30 minutes, 1.83 g of ethyl bromoacetate were introduced. Precipitating crystalline solid gradually made the mixture more viscous. After about 2 hours, the mixture solidified to a thick, unstirrable crystal slurry.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10](F)=[CH:9][CH:8]=3.[Li]CCCC.[CH:28](N1CCOCC1)=[O:29]>C1COCC1>[Br:1][C:2]1[CH:14]=[C:13]2[C:5](=[CH:4][CH:3]=1)[N:6]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:7]1[CH:8]=[CH:9][C:10]([CH:28]=[O:29])=[CH:11][C:12]2=1
Reactant: O=CN1CCOCC1
Reactant: COCCOCCn1c2ccc(F)cc2c2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCCn1c2ccc(Br)cc2c2cc(C=O)ccc21
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 65 %

Procedure:
To a solution of 3-bromo-6-fluoro-9-(2-(2-methoxyethoxy)ethyl)-9H-carbazole (3.4 g, 9.3 mmol) in dry THF (50 ml) was added n-BuLi (1.6 M, 8.7 ml, 13.9 mmol) at −78° C. The resulting mixture was stirred for 50 min at −78° C. and then added with N-formylmorpholine (1.86 ml, 18.6 mmol). The reaction mixture was allowed to warm to rt and stirred for 2 h before quenched with ammonia chloride solution. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by silica gel column chromatography eluting with 2:1 petroleum ether/ethyl acetate to give compound 7 in 65% yield. 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.53 (s, 1H), 8.02-8.00 (m, 1H), 7.80-7.77 (m, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.45 (dd, J=4.0 Hz, J=9.2 Hz 1H), 7.28-7.23 (m, 1H), 4.52 (t, J=5.6 Hz, 2H), 3.88 (t, J=5.6 Hz, 2H), 3.52-3.50 (m, 2H), 3.40 (d, J=2.8 Hz, 2H), 3.28 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 191.8, 159.3, 156.9, 145.2, 137.8, 128.8, 127.5, 124.4, 123.7, 123.7, 123.7, 122.8, 114.8, 114.5, 110.6, 110.5, 109.8, 106.7, 106.4, 72.1, 71.0, 69.5, 59.2, 43.9. HRMS (MALDI-TOF) m/z Calcd for C18H18FNO3 316.1343. Found 316.1340[M]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Br)cnc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.9 %

Procedure:
To a solution of 5-bromo-2-methylpyridin-3-amine (10.7 g, 57.5 mmol) in dichloromethane (575 mL) was added acetic anhydride (12 mL, 126.5 mmol) at 0° C. followed by triethylamine (22 mL, 158 mmol). The mixture was allowed to warm to ambient temperature and stirred for 18 hours at which point a further equivalent of acetic anhydride (6 mL, 63 mmol) was added. The mixture was stirred at ambient temperature for a further 72 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate (500 mL) and the organic phase washed with saturated aqueous sodium chloride (500 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown solid. This solid was triturated with 30% ethyl acetate in hexanes to yield N-(5-bromo-2-methylpyridin-3-yl)acetamide as an off-white solid (8.28 g, 63%). 1HNMR (400 MHz, CD3OD, δ): 8.31 (s, 1H), 8.18 (s, 1H), 2.43 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].[C:29]([CH:36]([NH2:39])C=O)(OC(C)(C)C)=O.[BH4-].[Na+]>CO>[NH2:39][CH2:36][CH2:29][NH:1][C@H:2]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)(C)OC(=O)C(N)C=O
Reactant: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3ccccc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NCCN[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3ccccc23)CC1
Reaction time: 3 h
Yield: 63.5 %

Procedure:
(2R)-2-Amino-3-(4-chlorophenyl)-1-(4-quinazolin-4-yl-piperazin-1-yl)-propan-1-one (free-base, 41 mg, 0.104 mmol) was stirred at room temperature with Boc-2-aminoacetaldehyde (16 mg, 0.104 mmol) in 0.7 mL methanol for 1 hour, after which NaBH4 (6 mg, 0.160 mmol) was added. The reaction mixture was stirred for 3 hours and then quenched with 1N NaOH. The reaction mixture was extracted with DCM, and the combined extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation. The crude residue was purified on silica (15:1 DCM/MeOH). The resulting Boc-amine intermediate was treated with 1.4 mL 4M HCl/dioxane and stirred at room temperature for 14 hours, after which the reaction mixture was diluted with ether. The solids were isolated by filtration with nitrogen pressure and dried under reduced pressure to give the desired product (29 mg, 51%) as the trihydrochloride salt. Rt 1.69. MS (CI+) [M+H]+ 439.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1)=[O:8].[C:25](Cl)(=[O:27])[CH3:26]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:26])[CH2:21][CH2:20]2)[S:5][C:6]=1[C:7](=[O:8])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1
Reactant: COc1ccc(C(=O)c2sc(NC3CCNCC3)nc2N)cc1F
Reactant: CC(=O)Cl
Product: COc1ccc(C(=O)c2sc(NC3CCN(C(C)=O)CC3)nc2N)cc1F
Yield: 77 %

Procedure:
[4-Amino-2-(piperidin-4-ylamino)thiazol-5-yl]-(3-fluoro4-methoxy-phenyl)methanone (0.125 g, 0.36 mmol) (Example 7) was treated with acetylchloride in a manner similar to Example 9 to give 100 mg (77% yield) of 1-[4-[4-amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidin-1-yl]ethanone. 1H NMR (DMSO−d6, 300 MHz) δ1.38 (dm, 2H, CH2), 1.92 (m, 2H, CH2), 2.02 (s, 3H, COCH3), 2.76 (t, 1H, NCH), 3.26 (t, 1H, NCH), 3.6-4.0 (broad, 1H, CH), 3.77 (m, 1H, NCH), 3.90 (s, 3H, OCH3), 4.22 (m, 1H, NCH), 7.23 (t, 1H, Aromatic), 7.47 (t, 1H, Aromatic), 7.50 (t, 1H, Aromatic), 7.9-8.5 (brd, 2H, 2NH), 8.69 (brd, 1H, NH). HRMS: (M+H)+: observed: 393.1396; calcd for 393.1391.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17](F)[C:16]=1[F:25].Cl>C1COCC1>[F:25][C:16]1[C:15]([F:14])=[CH:20][CH:19]=[C:18]([N+:21]([O-:23])=[O:22])[C:17]=1[O:13][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Oc1cccc2ccccc12
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1Oc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
Sodium hydride (60% oil dispersion) (2.77 g, 69.4 mmol) was added to a solution of 1-naphthol (10.00 g, 69.4 mmol) in THF (200 mL) while cooling in an ice bath. The mixture was stirred at 0° C. for 30 min and 1,2,3-trifluoro-4-nitrobenzene (12.28 g, 69.4 mmol) was added and the mixture was allowed to warm to room temperature. After 2 hrs, the reaction mixture was poured into a mixture of ice and 10% aqueous HCl and was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was purified by flash chromatography (hexane:ethyl acetate) to give the title compound (14.5 g, 69.4%). 1H NMR (400 MHz, chloroform-d) 6d ppm 8.31-8.45 (m, 1H), 7.82-7.99 (m, 2H), 7.54-7.66 (m, 3H), 7.30 (t, 1H), 7.17-7.26 (m, 1H), 6.61 (d, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:18].[H][H]>[Pt]=O.CO>[NH2:15][C:12]1[CH:13]=[CH:14][C:7]2[N:8]([CH:11]=1)[C:9](=[O:10])[C:4]([CH2:3][CH2:2][Cl:1])=[C:5]([CH3:18])[N:6]=2
Reactant: [H][H]
Reactant: Cc1nc2ccc([N+](=O)[O-])cn2c(=O)c1CCCl
Agent: O=[Pt]
Solvent: CO
Product: Cc1nc2ccc(N)cn2c(=O)c1CCCl

Procedure:
A mixture of 40 parts of 3-(2-chloroethyl)-2-methyl-7-nitro-4H-pyrido[1,2-a]pyrimidin-4-one and 240 parts of methanol was hydrogenated at normal pressure and at room temperature with 0.5 parts of platinum oxide. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in acetonitrile and 2-propanol. The salt was filtered off and dissolved in water while heating. The solution was treated with activated charcoal. The latter was filtered off over Hyflo and the filter-cake was washed with water. The filtrate was stirred in a dilute ammonium hydroxide solution. The precipitated product was filtered off, washed with water and with petroleumether, and dried, yielding 19.4 parts of 7-amino-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 185° C. (intermediate 9).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[NH:5][N:4]=1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([CH3:28])[CH:27]=1)[CH3:20].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([N:5]2[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[CH:7][C:3]([C:2]([F:1])([F:17])[F:18])=[N:4]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1)[CH3:20]
Reactant: CCOc1cc(C)cc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)NCc1cc(C(F)(F)F)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1cc(C)cc(-n2nc(C(F)(F)F)cc2CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.6 %

Procedure:
To a mixture of tert-butyl (3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (251 mg, 0.947 mmol, 1 equiv.), 3-ethoxy-5-methylphenylboronic acid (341 mg, 1.89 mmol, 2 equiv.) and copper acetate (259 mg, 1.42 mmol, 1.5 equiv.) in dichloromethane was added pyridine (151 mg, 0.151 mL, 1.89 mmol, 2 equiv) and the mixture was stirred for 2 d at room temperature. The reaction mixture was filtered over silica gel, the filter cake was washed with 250 mL of dichloromethane and the filtrate was evaporated to give tert-butyl (1-(3-ethoxy-5-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (354 mg, 94%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]1)=[O:13])[CH:6]=[CH:5]2.[CH3:21][C:22]([CH3:32])([CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:23]O>>[CH3:23][C:22]([CH3:32])([CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:21][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:14]1[CH2:15][CH2:16][CH:17]([CH3:20])[CH2:18][CH2:19]1)=[O:13])[CH:6]=[CH:5]2
Reactant: CC(C)(CO)CN1CCCCC1
Reactant: CC1CCN(C(=O)c2ccc3cc(O)ccc3c2)CC1
Product: CC1CCN(C(=O)c2ccc3cc(OCC(C)(C)CN4CCCCC4)ccc3c2)CC1

Procedure:
The title compound was synthesised from (6-hydroxy-naphthalen-2-yl)-(4-methyl-piperidin-1-yl)-methanone (intermediate B) and 2,2-dimethyl-3-piperidin-1-yl-propan-1-ol (commercially available) according to the procedure described for the synthesis of Example 1.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[N:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][N:4]=1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[CH3:1][N:2]([CH3:16])[C:3]1[N:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:23])[CH2:18]3)[CH2:11][CH2:10]2)=[CH:5][N:4]=1
Reactant: CN(C)c1ncc(C2CCC(=O)CC2)cn1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CN(C)c1ncc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(2-dimethylamino-pyrimidin-5-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1>>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:26]4[CH:27]=[CH:28][O:24][CH:25]=4)=[CH:3][CH:4]=3)[C:9]([CH3:23])=[CH:10][CH:11]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: OB(O)c1ccoc1
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(Br)cc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(-c2ccoc2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 35 using 1-(4-bromophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole instead of 1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole and 3-furanboronic acid instead of 2-furanboronic acid in step 4.