Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20].O>C(O)(=O)C>[F:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(F)cc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(F)cc2[N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 97 %

Procedure:
To a suspension of 4′-fluoro-p-toluenesulfonanilide (486.6 g (1.80 mol) in acetic acid (955 ml), 97% fuming nitric acid (128.6 g (1.98 mol) was added dropwise, keeping the inner temperature at 45° C., over a period of 40 minutes. After completion of the addition, the reaction mixture was stirred at 50° C. for 2 hours and left to cool to room temperature. Water (2000 ml) was then added and the mixture was stirred for 30 minutes. The crystals separated were filtered and washed with water to give 543.5 g (97%) of 4′-fluoro-2′-nitro-p-toluenesulfonanilide as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:13]=[C:14]([N:18]([CH3:23])[C:19](=[O:22])[CH:20]=[CH2:21])[CH:15]=[CH:16][CH:17]=3)[N:9]=[C:10](I)[C:3]=12.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:13]=[C:14]([N:18]([CH3:23])[C:19](=[O:22])[CH:20]=[CH2:21])[CH:15]=[CH:16][CH:17]=3)[N:9]=[C:10]([C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=3)[C:3]=12
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: C=CC(=O)N(C)c1cccc(-n2nc(I)c3c(N)ncnc32)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: O
Product: C=CC(=O)N(C)c1cccc(-n2nc(-c3ccc(Cl)cc3)c3c(N)ncnc32)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a stirred solution of N-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl) phenyl)-N-methylacrylamide (50) (147 mg, 0.35 mmol) and 4-chlorophenylboronic acid (66 mg, 0.42 mmol) in DME/H2O (4 mL/1 mL) were added Pd(dppf)Cl2(14 mg, 0.018 mmol) and K3PO4.3H2O (280 mg, 1.05 mmol). The resulting mixture was purged with N2 (3×) and stirred at 80° C. overnight. Solvents were removed in vacuo. The residue was pre-purified by flash chromatography (silica gel, 0 to 10% MeOH in DCM with 0.3% TEA) and followed by prep HPLC to provide N-(3-(4-amino-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-N-methylacrylamide (51) (39 mg, 28%) as a white solid. LC-MS (ESI): m/z (M+1) 405.1. 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.14 (s, 1H), 7.76 (d, J=8.3 Hz, 2H), 7.62 (m, 3H), 7.28 (m, 1H), 6.17 (m, 2H), 5.59 (m, 1H), 3.30 (s, 3H).
Reaction SMILES: [CH3:1][CH2:2][O:3][CH2:4][C:5](Cl)=[O:6].[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][N:10]=1.CN1CCOCC1>ClCCl>[CH2:2]([O:3][CH2:4][C:5]([NH:16][NH:15][C:13](=[O:14])[C:12]1[CH:17]=[CH:18][C:9]([Cl:8])=[N:10][CH:11]=1)=[O:6])[CH3:1]
Reactant: NNC(=O)c1ccc(Cl)nc1
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOCC(=O)NNC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
(2-Ethoxy)-acetyl chloride [(1.72 g, 13.99 mmol), Tett. Lett., 35, (39), 7269; 1994)] was added to an ice-cold solution of 6-chloronicotinic acid hydrazide (2 g, 11.66 mmol) and N-methylmorpholine (1.92 mL, 17.49 mmol) in dichloromethane (60 mL) and the mixture was stirred at room temperature for 18 hours. The mixture was then washed with citric acid, sodium hydrogen carbonate solution and brine and the solvent was evaporated under reduced pressure to yield some title product as a white solid, 880 mg. The combined aqueous washings were extracted with ethyl acetate (×2) and the combined organic solutions were dried over sodium sulfate and concentrated in vacuo to afford a further crop of title compound as a pale yellow solid, 1.6 g (total yield of 83%).
Reaction SMILES: Cl[CH2:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.O>CN(C)C=O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3](=[O:13])[CH2:2][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:7][CH:8]=1
Reactant: O=C(CCl)CCc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(Cl)cc1)Cn1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
1-Chloro-4-(4-chlorophenyl)-2-butanone (110 g.) was added portionwise over half an hour to a stirred suspension of imidazole (175 g) in dimethylformamide (150 ml) at 0° C. and the mixture stirred overnight at ambient temperature. The resulting solution was poured into water (1500 ml) with seeding at the first sign of turbidity, and the precipitate filtered off and washed well with water and hexane. Chromatography of the product on silica gel (1 Kg.), eluting with 7% methanol in methylene chloride gave 100 g of 1-[4-(4-chlorophenyl)butan-2-on-1-yl]imidazole.
Reaction SMILES: [O:1]=[S:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([CH:14]([CH3:16])[CH3:15])[CH2:4][O:3]1.I([O-])(=O)(=O)=[O:18].[Na+]>C(#N)C.O.[Ru](Cl)(Cl)Cl>[O:1]=[S:2]1(=[O:18])[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@@H:5]([CH:14]([CH3:16])[CH3:15])[CH2:4][O:3]1
Reactant: CC(C)[C@H]1COS(=O)N1Cc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)[C@H]1COS(=O)(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To an ice-cooled solution of (4S)-2-oxo-3-benzyl-4-isopropyl-1,2,3-oxathiazolidine (6.00 g, 25.07 mmol) in acetonitrile (45 mL) and water (45.0 mL) was added ruthenium chloride (5.20 mg, 0.025 mmol) followed by sodium periodate (8.04 g, 37.6 mmol). The mixture was stirred for 1 h as ice bath melted and the reaction was gradually warmed to room temperature. The mixture was extracted with ether (3×50 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4), filtered, then concentrated. The resulting oil was purified by silica gel flash column chromatography to give the title compound (1.9 g) as a colorless oil. LCMS m/z=256.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 0.86 (d, J=7.1 Hz, 3H), 0.90 (d, J=7.1 Hz, 3H), 1.83-1.95 (m, 1H), 3.41-3.45 (m, 1H), 4.23-4.28 (m, 2H), 4.39-4.44 (m, 2H), 7.35-7.43 (m, 5H).
Reaction SMILES: F[CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=2[CH3:19])[C:6]2[CH:20]=[C:21]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:22]=[C:23]([B:24]([OH:26])[OH:25])[C:5]=2[N:4]=1.C(#N)C.[OH2:36]>>[OH:36][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[C:10]=2[CH3:19])[C:6]2[CH:20]=[C:21]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:22]=[C:23]([B:24]([OH:26])[OH:25])[C:5]=2[N:4]=1
Reactant: O
Reactant: Cc1c(Cn2c(CF)nc3c(B(O)O)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Solvent: CC#N
Product: Cc1c(Cn2c(CO)nc3c(B(O)O)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 48 h
Yield: 46 %

Procedure:
(2-(fluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid (40 mg, 0.089 mmol) was dissolved in Water+0.1% TFA (2.5 mL) and Acetonitrile+0.1% TFA (2.5 mL) in a 20 mL scintillation vial. The mixture was stirred at 70° C. for 2 days, solution was evaporated and taken up in 50% water/acetonitrile and was purified by reversed phase HPLC eluted with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (20-55%) over 12 minutes. The appropriate fractions were collected and evaporated to yield (2-(hydroxymethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid (18.5 mg, 0.041 mmol, 46.0% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.59 (s, 3H) 3.11-3.21 (m, 4H) 3.75-3.86 (m, 4H) 5.04 (s, 2H) 5.88 (s, 2H) 6.75 (d, 1H) 7.03 (d, J=2.27 Hz, 1H) 7.25 (t, J=7.83 Hz, 1H) 7.65 (d, J=7.83 Hz, 1H) 7.72 (br. s., 1H); LC/MS: MS (ES+) m/e 450 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15](Cl)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:18][C@@H:19]1[CH2:24][N:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][CH3:33])=[CH:28][CH:27]=2)[CH2:22][C@H:21]([CH3:34])[N:20]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([N:32]([CH3:33])[C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:23]4[CH2:24][C@H:19]([CH3:18])[N:20]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:21]([CH3:34])[CH2:22]4)=[CH:31][CH:30]=3)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CNc1ccc(CN2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)N(C)c1ccc(CN2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The acid chloride from step 1 was taken up in DCM (3 mL) and added to a solution of 1,1-dimethylethyl (2R,6S)-2,6-dimethyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D9) (0.23 g, 0.693 mmol) in DCM (2 mL). Triethylamine (0.193 mL, 1.386 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM and washed with water. The aqueous layer was re-extracted with DCM (×2) and the combined organics were dried and concentrated. The crude product was purified by column chromatography. Elution with 0-50% EtOAc/petroleum yielded the title compound as a white foam (0.331 g). δH (CDCl3, 400 MHz) 7.89 (2H, m), 7.36 (1H, m), 7.26 (1H, m), 7.19 (2H, m), 7.10 (2H, t), 6.99 (2H, m), 4.00 (2H, m), 3.53 (3H, s), 3.34 (2H, s), 2.58 (3H, s), 2.44 (2H, d), 2.05 (2H, m), 1.44 (9H, s), 1.18 (6H, d). MS (ES): MH+ 547.3.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)(=O)=O)=CC=1.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:20][C:16]1([CH3:19])[O:15][CH2:14][CH:13]([CH2:12][NH:26][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:18][O:17]1
Reactant: NC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)OC2)cc1
Product: CC1(C)OCC(CNC2CCCC2)CO1
Temperature: 80 °C
Yield: 93.8 %

Procedure:
A mixture of 1.5 g (5 mmol) of (2,2-dimethyl-1,3-dioxan-5-yl)methyl 4-methylbenzenesulfonate and 10 mL (101 mmol) of cyclopentylamine is heated for 12 hours at 80° C. The medium is concentrated under reduced pressure and then taken up in 200 mL of Et2O, washed with water (2×50 mL), dried over Na2SO4 and concentrated under reduced pressure. 1 g of N-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]cyclopentanamine is obtained in the form of an oil, which is used in the following step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[CH:31]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>O1CCCC1>[CH:31]1([C:36]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=5)[CH:14]=[CH:15][CH:16]=4)=[N:6][N:5]3[CH:30]=2)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: O=C(Cl)C1CCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CCCC4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Yield: 56.9 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol), cyclopentanecarbonyl chloride (53 μL, 0.435 mmol), triethylamine (75 μL, 0.544 mmol) and tetrahydrofuran (5 mL) as starting materials and in the same manner as in Example 388, the title compound (105 mg, 57%) was obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[C:13]Cl)=[CH:7][CH:6]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[C:13][N:16]=[N+:17]=[N-:18])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(CC#CCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(CC#CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.1 %

Procedure:
4-(3-Chloroprop-2-ynyl)phenylacetic acid methyl ester (5.3 g, 0.023M) was dissolved in dry dimethylformamide (30 ml) with sodium azide (1.7 g, 1.1 molar equivalents) and stirred at room temperature for 14 h. The reaction mixture was diluted with water (200 ml) and washed with dichloromethane (2×150 ml). The combined organic layers were washed with water (2×100 ml) and brine (1×100 ml) then dried (Na2SO4), filtered and concentrated in vacuo to give a residue which was purified by passage down a silica gel column, using as eluents 20% dichloromethane in hexane and finally neat dichloromethane, to give the required product (5.3 g) as a colourless oil. δ (360 MHz, CDCl3) 3.63 (2H, s, CH2CO2CH3), 3.70 (3H, s, CH2CO2CH3), 4.14 (2H, s, CH2N3), 7.24 (2H, d, J=8.4 Hz, ArH), 7.42 (2H, d, J=8.4 Hz, ArH); m/e 229 (M+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][CH2:24][CH2:25]Cl>CS(C)=O.O>[CH2:7]([NH:11][CH2:25][CH2:24][CH2:23][O:22][C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1)[CH2:8][CH2:9][CH3:10]
Reactant: ClCCCOc1ccc2ccccc2c1
Reactant: CCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCNCCCOc1ccc2ccccc2c1
Temperature: 135 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-butylamine (0.34 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 135° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-butyl)-(3-(naphthalen-2-yloxy)propyl)amine, solid, m.p. 112° C., (yield 0.55 gm, 94.5%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)=[O:28])=[CH:22][C:20]=2[N:21]=1.O1CCOCC1>CN(C)C=O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:19]3[S:18][C:17]([NH:16][C:2]4[C:11]5[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=5)[N:5]=[CH:4][N:3]=4)=[N:21][C:20]=3[CH:22]=2)=[O:28])=[CH:31][C:32]=1[C:37]([F:39])([F:38])[F:40]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1nc2cc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)ccc2s1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3nc4cc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)ccc4s3)c2cc1OC

Procedure:
1-(4-Chloro-3-trifluoromethylphenyl)-3-[2-(6,7-dimethoxyquinazolin-4-ylamino)benzothiazol-5-yl]urea was prepared from 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 29 mg, 0.13 mmol) and 1-(2-aminobenzothiazol-5-yl)-3-(4-chloro-3-trifluoromethylphenyl)urea (Intermediate 5, 50 mg, 0.13 mmol) according to GP 1. Dimethylformamide was used as a solvent instead of dioxane. After removal of the solvent in vacuo, the residue was subjected to silica gel chromatography applying a dichloromethane-methanol gradient. The crude product was dissolved in dimethylformamide (2 mL) and water was added (2 mL). After storing in the fridge overnight, the resulting precipitate was filtered off, washed with water and dried (yellow solid, 7 mg, 12 μmol, 9%). LC/ESI-MS: m/z=575 [M(35Cl)+H]+; m/z=573 [M(35Cl)−H]−; Rt=4.17 min.
Reaction SMILES: [ClH:1].[F:2][C:3]1([F:18])[CH2:5][CH:4]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][NH:13][CH2:12][CH2:11]2.C(OC(=O)[NH:25][C@H:26]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1)[CH3:27])(C)(C)C.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[ClH:1].[F:18][C:3]1([F:2])[CH2:5][CH:4]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C@@H:26]([NH2:25])[CH3:27])=[CH:29][CH:30]=1)[CH2:12][CH2:11]2
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)cc1
Reactant: FC1(F)CC1COc1ccc2c(c1)CCNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@H](N)c1ccc(CN2CCc3cc(OCC4CC4(F)F)ccc3C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 800 mg (2.94 mmol) 6-(2,2-difluoro-cyclopropylmethoxy)-1,2,3,4-tetrahydro-isoquinoline hydrochloride (example XXXII.2) and 806 mg (3.23 mmol) [(S)-1-(4-formyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (example II) in 8 mL THF are added 504 μL (8.81 mmol) AcOH and the mixture is stirred at r.t. for 10 min. After that time, the resulting mixture is cooled to 0° C. and 934 mg (4.41 mmol) sodium triacetoxyborohydride are added and the reaction mixture is stirred at r.t. for 2 h. After that time, the reaction is quenched by addition of 500 μl water, the solvent is removed and and the residue is purified by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12]>C(O)C.C(O)(=O)C.[Pt]>[NH2:9][C:4]1[C:5]([Cl:8])=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[OH:12]
Reactant: O=[N+]([O-])c1c(Cl)ccc(Cl)c1O
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1c(Cl)ccc(Cl)c1O
Yield: 99.7 %

Procedure:
A yellow solution of 2,5-dichloro-6-nitrophenol (10.0 g, 48.0 mmol) in ethanol (200 mL) and acetic acid (13.8 mL) at 0° C. was catalytically reduced in the presence of 5% platinum on charcoal (0.15 g) under an atmosphere of hydrogen (25 psi) for 1 hour in a Parr hydrogenator. The resultant colorless solution was filtered and concentrated under reduced pressure (15 torr). The residue was then dried under high vacuum (0.02 torr) overnight to yield 8.52 g (100%) of 2-amino-3,6-dichlorophenol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([NH:13]C(OCC[Si](C)(C)C)=O)[CH:10]([C:23](=[O:32])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>CCOCC>[NH2:13][CH:11]1[CH:10]([C:23](=[O:32])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)OCC[Si](C)(C)C)C(C(=O)Nc2cccc(F)c2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(N)C(C(=O)Nc2cccc(F)c2)C1
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To 3-(3-Fluoro-phenylcarbamoyl)-4-(2-trimethylsilanyl-ethoxycarbonylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (1700.00 mg; 3.64 mmol; 1.00 eq.) was added of TBAF (2851.67 mg; 10.91 mmol; 3.00 eq.) (1.0M in THF 11 ml). The resulting mixture was stirred overnight. The reaction mixture was poured into water, washed with brine, then 5% NaHCO3, brine, dried and concentrated to give the crude, which was added of ether (5 ml). The precipitated white solid was filtered to afford the title compound (710 mg, 60.4%).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:16][CH:13]2[CH2:15][CH2:14]2)[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: NC1CC1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Product: CSc1nc(Cl)c(C=O)c(NC2CC2)n1

Procedure:
Prepared as described above in Example 2 starting from 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and cyclopropylamine to give the title compound 4-chloro-6-cyclopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 0.68 (m, 2H), 0.90 (m, 2H), 2.58 (s, 3H), 3.07 (m, 1H), 9.20 (br s, 1H), 10.28 (s, 1H). LC MS (m/e)=244 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O(C(C)(C)C)[Na]>C1(C)C=CC=CC=1>[C:2]1([S:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1ccccc1
Reactant: Brc1ccccc1
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: c1ccc(Sc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A 50 mL of reactor equipped with magnetic stir bar was charged with 252 mg (0.27 mmol) of {[(t-Bu)2P(OH)]2PdCl}2, 2.90 g (18.47 mmol) of bromobenzene, 1.98 g (18.0 mmol) of PhSH and 3.46 g (36.0 mmol) of NaO—tBu in 20.0 mL of toluene. The resulting mixture was refluxed for 15 h before the mixture was cooled to room temperature and quenched with 100 mL of H2O. The mixture was transferred to a separatory funnel, and extracted with EtOAc (2×200 mL). The layers were separated, and organic layer was washed with H2O (100 mL), brine (150 mL), and dried over mgSO4, filtered, and the solvents removed from the filtrate by rotary evaporation. The product was isolated by distillation. The final product was obtained as a colorless oil (2.24 g, 66% yield).
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=C3C=2CN(C)C3=O)C=N1.[NH2:50][C:51]1[C:52]([C:67]([NH:69][CH3:70])=[O:68])=[N:53][C:54]([C:57]2[CH:58]=[N:59][N:60]([CH2:63][CH2:64][CH2:65][OH:66])[C:61]=2[CH3:62])=[CH:55][CH:56]=1>>[OH:66][CH2:65][CH2:64][CH2:63][N:60]1[C:61]([CH3:62])=[C:57]([C:54]2[N:53]=[C:52]([C:67](=[O:68])[NH:69][CH3:70])[C:51]([NH:50][C:26]3[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:25]=3)=[CH:56][CH:55]=2)[CH:58]=[N:59]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1nc(-c2cnn(CCCO)c2C)ccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4C)nc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 59 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 3-Amino-6-[1-(3-hydroxypropyl)-5-methyl-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 35C, 177 mg, 644 μmol) to afford 270 mg of the title compound (59%). 1H NMR (400 MHz, CD3OD) d 8.59-8.68 (m, 1H), 8.30 (s, 1H), 8.03 (s, 1H), 7.76-7.86 (m, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.01 (s, 1H), 6.88 (d, J=8.1 Hz, 1H), 4.26 (t, J=7.1 Hz, 2H), 4.05 (quin, J=7.3 Hz, 4H), 3.88 (s, 3H), 3.53-3.60 (m, 2H), 3.25 (d, J=21.0 Hz, 2H), 2.92-2.98 (m, 3H), 2.63 (s, 3H), 2.04 (t, J=6.7 Hz, 2H), 1.25 (t, J=7.1 Hz, 6H). MS (ESI): m/z=677.21 [M+H]+. UPLC: tR=3.8 min (ZQ3: polar—5 min).