Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:25])([CH3:24])[C:3]([NH:5][C:6]1[S:7][C:8]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1)=[O:4].[CH:26]1([CH2:31][C:32](Cl)=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)CC)C>C(Cl)Cl>[CH:26]1([CH2:31][C:32]([NH:1][C:2]([CH3:25])([CH3:24])[C:3]([NH:5][C:6]2[S:7][C:8]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)=[O:4])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: CC(C)(N)C(=O)Nc1nc(-c2ccc(F)cc2)c(N2CCOCC2)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)CC1CCCC1)C(=O)Nc1nc(-c2ccc(F)cc2)c(N2CCOCC2)s1

Procedure:
2-Amino-N-[4-(4-fluoro-phenyl)-5-morpholin-4-yl-thiazol-2-yl]-2-methyl-propionamide (1 eq), cyclopentyl acetyl chloride (1.05 eq) and triethyl amine (3 eq) were stirred as a solution in DCM (5 mL). Desired product was isolated from reaction mixture by silica gel chromatography. LCMS Method 10 Rt=1.48 (M+1=475.1, M−1=473.1), HRMS; expected=474.2101, found=474.2116. 1H NMR (400 MHz, DMSO-D6) 1.07-1.18 (m, 2H) 1.38 (s, 5H) 1.42-1.51 (m, 2H) 1.52-1.60 (m, 2H) 1.62-1.73 (m, 2H) 2.11 (s, 3H) 2.78-2.88 (m, 4H) 3.69-3.78 (m, 4H) 7.23 (t, J=8.91 Hz, 2H) 8.01 (s, 1H) 8.13 (dd. J=8.59, 5.81 Hz, 2H) 11.45 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8])=O.C(N(CC)CC)C.ClC(OCC)=O>CC(C)=O>[Cl:1][CH2:2][C:3]1[O:8][C:7](=[O:9])[C:6]([CH3:11])([CH3:10])[N:5]=1
Reactant: CC(C)(NC(=O)CCl)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)N=C(CCl)OC1=O
Temperature: 25 °C

Procedure:
To stirring mixture of 2-(2-chloro acetylamino)-2-methyl propionic acid (18.04 g, 0.10 mol), triethylamine (11.13 g, 0.11 mol), and 100 mL of acetone cooled with an ice bath was added ethyl chloroformate (10.52 mL, 0.11 mol) over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 2 hours. The mixture was then filtered, and the filtrate was concentrated under vacuum. Hexane (200 mL) was added to the residue and the mixture was filtered. After removal of the solvent under vacuum, the residue was distilled under reduced pressure (bp 59-60° C. at 7 mmHg) to give a colorless oil. A yield of 13.18 g (82%) was obtained.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)[CH2:3][CH2:4]Br.[I-:18].[Na+]>CC(C)=O>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)[CH2:3][CH2:4][I:18]
Reactant: CC(=CCCc1ccc2c(c1)OCO2)CCBr
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=CCCc1ccc2c(c1)OCO2)CCI

Procedure:
3-Methyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide [VI; Ar is 3,4-methylenedioxyphenyl, R is CH3 ] was prepared from 19.0 g. of 3-methyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl bromide (Preparation C3) and 10.5 g. of sodium iodide in 125 ml. of acetone, to give 21 g. of product as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:11]=[C:10]([CH:12](O)[CH3:13])[C:9]2[C:5](=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:8]=2)[CH:4]=1.C(Br)(Br)(Br)[Br:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCC>[Br:26][CH:12]([C:10]1[C:9]2[C:5](=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:8]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:11]=1)[CH3:13]
Reactant: CC(O)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(Br)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (±)-1-(5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethanol (444 mg, 1.23 mmol) and carbon tetrabromide (613 mg, 1.85 mmol) in tetrahydrofuran (5 mL) at 0° C. was added triphenylphosphine (485 mg, 1.85 mmol). The resulting solution was stirred at room temperature for 30 min. The reaction was diluted with several volumes of pentane and filtered to remove undissolved solids. The organics were concentrated and purified by column chromatography (4%→6% EtOAc/Hex) to give 284 mg (55%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 8.27 (s, 1H), 8.00 (s, 1H), 7.58 (s, 1H), 5.90 (q, J=7.0 Hz, 1H), 5.77 (qAB, JAB=10.4 Hz, 2H), 3.68 (m, 2H), 2.23 (d, J=7.0 Hz, 3H), 0.95 (m, 2H), −0.03 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 146.4, 134.2, 124.9, 124.7 (q, J=32 Hz), 124.6 (q, J=273 Hz), 121.6, 119.7 (q, J=4.8 Hz), 119.3 (q, J=2.9 Hz), 82.2, 68.1, 43.7, 25.5, 18.0, −1.4.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([NH:25][C:26](=[O:40])[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)=[C:29]([F:39])[CH:28]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22].NN>CO.C1COCC1>[NH2:3][CH2:12][C@@H:13]([NH:25][C:26](=[O:40])[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)=[C:29]([F:39])[CH:28]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22]
Reactant: Cn1nccc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1F
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nccc1-c1ccc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-3-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzamide (112 mg, 0.2 mmol) in MeOH/THF (2 mL, 1:1) at RT was added hydrazine (0.12 mL, 3.93 mmol). After stirring for 18 h at RT, the reaction solution was concentrated under vacuum and purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>C(Cl)Cl>[CH2:15]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(Cc2ccccc2)C1
Reaction time: 8 h
Yield: 34.4 %

Procedure:
To a solution of (S)-tert-butyl piperidin-3-ylcarbamate (2.0 g, 10.0 mmol) and benzaldehyde (1.3 g, 12.0 mmol) in CH2Cl2 under nitrogen was added NaBH(OAc)3 (4.2 g, 20.0 mmol) and the reaction was stirred for overnight. The mixture was diluted with CH2Cl2 (50 mL) and ice cooled water (20 mL). The CH2Cl2 layer was separated and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined CH2Cl2 layer was dried over Na2SO4 and evaporated in vacuo to give the crude product which was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to afford (1.0 g, 34%) of the titled intermediate. LC-MS: m/z [M+1]=291.
Reaction SMILES: CC1N(S(O)(=O)=[O:7])C(=O)C1.C(N(CCCC)CCCC)CCC.ON1C2C=CC=CC=2N=N1.[CH:34]1([N:40]=[C:41]=[N:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:41]([NH:40][CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)([NH:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:7]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC1CC(=O)N1S(=O)(=O)O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
[3S-[3α(Z),4β]]-3-[[(2-Amino-4-thiazolyl)-](1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), 0.93 g of tributylamine, 0.1 g of N-hydroxybenzotriazole and 0.05 g of 4-dimethylaminopyridine were dissolved in 20 ml of dimethylformamide and a solution of 1.06 g of dicyclohexylcarbodiimide in 5 ml of dimethylformamide was added. After stirring for 15 minutes at room temperature, a solution of 0.94 g Girard Reagent P in 20 ml of dimethylformamide was added. After 3 hours of stirring, formed dicyclohexylurea was filtered off and the dimethylformamide of the filtrate was distilled off. Addition of 50 ml of tetrahydrofuran to the residue yielded 1.8 g of crude product, which was purified by column chromatography on HP-20 using water as an eluent, yielding 0.63 g of product, melting point 235° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[N:13]=[C:14]([CH3:17])[S:15][CH:16]=2)[CH:7]=[C:6]([F:18])[C:3]=1[CH2:4][OH:5].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32](Cl)=[O:33])[C@H:28]([CH2:35][CH3:36])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[N:13]=[C:14]([CH3:17])[S:15][CH:16]=2)[CH:7]=[C:6]([F:18])[C:3]=1[CH2:4][O:5][C:32]([N:29]1[CH2:30][CH2:31][N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH2:27][C@H:28]1[CH2:35][CH3:36])=[O:33]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Reactant: Cc1nc(COc2cc(F)c(CO)c(Cl)c2)cs1
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)cc(OCc2csc(C)n2)cc1Cl
Yield: 75 %

Procedure:
This compound was prepared from 2-chloro-6-fluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (582 mg; 75%); MS (ISP): 528.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH2:29])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:30](=O)[CH3:31].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:30][CH3:31])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNc1nn(C(=O)OC(C)(C)C)c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a stirred mixture of 13.40 g (25.74 mmol) 3-amino-5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-1H-indazole-1-carboxylic acid tert-butyl ester, from Synthetic Example 18, in 335 mL dry methanol, was added 2.19 mL acetaldehyde and 2.06 mL glacial acetic acid and the resulting mixture was stirred overnight at room temperature. The reaction was cooled (ice bath) before 3.24 g sodium cyanoborohydride was added in three portions. The mixture was stirred overnight at room temperature before the reaction was concentrated to roughly half volume under vacuum. The residue was partitioned between EtOAc and saturated aqueous sodium hydrogen carbonate solution and the organic extract washed with saturated aqueous sodium chloride solution and concentrated under vacuum. The residue was taken up in hot EtOAc and allowed to cool to room temperature before being triturated with diisopropyl ether. The stirred suspension was cooled (ice bath), filtered and the crude product washed with diisopropyl ether. The product was dried under vacuum to afford 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-3-(ethylamino)-1H-indazole-1-carboxylic acid tert-butyl ester (8.25 g, 76.6%) (Cpd. No. 117, Table 2). 1H-NMR (DMSO-D6, 300 MHz): δ=9.54 (br s, 1H), 7.86 (d, 1H), 7.73 (m, 1H), 7.41 (dd, 1H), 6.82 (t, 1H), 4.47 (s, 1H), 3.26-3.34 (partially obscured by solvent, m, 2H), 2.02 (s, 6H), 1.57 (s, 9H), 1.21 (t, 3H) ppm.
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][C:8]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:29][C:28]([CH2:52][C:53]#[N:54])([N:30]4[CH:34]=[C:33]([C:35]5[C:36]6[CH:43]=[CH:42][N:41](COCC[Si](C)(C)C)[C:37]=6[N:38]=[CH:39][N:40]=5)[CH:32]=[N:31]4)[CH2:27]3)[CH2:22][CH2:21]2)=[O:19])[CH:9]=1.C(N(CC)CC)C.[CH3:62][CH:63]([NH2:65])[CH3:64]>C(Cl)Cl>[CH:63]([NH:65][CH2:7][C:8]1[N:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=[C:10]([C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:29][C:28]([CH2:52][C:53]#[N:54])([N:30]4[CH:34]=[C:33]([C:35]5[C:36]6[CH:43]=[CH:42][NH:41][C:37]=6[N:38]=[CH:39][N:40]=5)[CH:32]=[N:31]4)[CH2:27]3)[CH2:24][CH2:25]2)=[O:19])[CH:9]=1)([CH3:64])[CH3:62]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)c6cc(CO)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Reactant: CC(C)N
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NCc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
Methanesulfonyl chloride (2.8 0.036 mmol) in methylene chloride (0.20 mL) was added to a mixture of {1-(1-{[6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (21 mg, 0.030 mmol, prepared as in Example 376, Step E) and triethylamine (8.4 μL, 0.060 mmol) in methylene chloride (1.0 mL) at 0° C. After 15 minutes, 2-propanamine (20 μL, 0.3 mmol) was added. The mixture was then heated to 40° C. After 1.5 hours, additional 2-Propanamine (20 μL, 0.3 mmol, Aldrich) was added and the reaction heated for a total of 3 hours at this temperature. The mixture was concentrated in vacuo. The residue was stirred for 1 hour in a 1:1 mixture of TFA/DCM, then concentrated again. The residue was redissolved in MeOH (1.0 mL) and ethylenediamine (0.2 mL) was added. The product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: 11.6 mg (63%); LC-MS: 608.4 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.15 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.97 (s, 1H), 7.61 (d, 1H), 7.07 (d, 1H), 41.2-4.02 (m, 1H), 3.94 (s, 2H), 3.75 (dd, 2H), 3.63-3.45 (m, 5H), 3.31-3.22 (m, 1H), 3.16-3.06 (m, 1H), 2.75 (septet, 1H), 2.61-2.53 (m, 1H), 1.84-1.75 (m, 1H), 1.70-1.60 (m, 1H), 1.36-1.19 (m, 2H), 1.01 (d, 6H). 19F NMR (400 MHz, DMSO-d6): δ −69.46 (s, 3F).
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][N:4]=1.[NH2:16][NH2:17]>C(O)(C)C>[NH:16]([C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][N:4]=1)[NH2:17]
Reactant: CSc1nnc(-c2ccccc2)c(=O)[nH]1
Reactant: NN
Solvent: CC(C)O
Product: NNc1nnc(-c2ccccc2)c(=O)[nH]1

Procedure:
To 3-(methylthio)-6-phenyl-1,2,4-triazin-5(4H)-one (4.3 g) in isopropyl alcohol (40 mL) was added hydrazine (6.41 g, 0.200 mol). The reaction mixture was refluxed for 10 h. After cooling, the crystalline solid formed was filtered and washed with isopropyl alcohol. The crystalline solid was collected and dried in vacuo to afford the desired product. Analytical LCMS: (M+H)+=204.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:35])[C:15]2[O:21][C:20]3[C:22]([Cl:31])=[CH:23][C:24]([NH:26][C:27](=[O:30])[CH2:28]Cl)=[CH:25][C:19]=3[CH2:18][S:17](=[O:33])(=[O:32])[C:16]=2[CH:34]=1)=[O:11]>CN(C=O)C>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:35])[C:15]2[O:21][C:20]3[C:22]([Cl:31])=[CH:23][C:24]([NH:26][C:27](=[O:30])[CH2:28][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:32])(=[O:33])[C:16]=2[CH:34]=1)=[O:11]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CN3CCN(C)CC3)cc(Cl)c1O2

Procedure:
N-Methyl piperazine (0.140 g, 0.675 mmol) was added to a solution of Example 133 (0.3 g, 1 mmol) in DMF (1 mL) and refluxed for 1.5 h. The reaction mixture was concentrated, treated with water and filtered to obtain the crude title compound, which was purified using flash chromatography (silica gel). Yield: 0.237 g, (70%); 1H NMR (DMSO-d6): δ 2.2 (s, 3H, CH3), 2.4 (s, 4H, 2CH2), 2.8 (s, 4H, 2CH2), 3.2 (s, 2H, CH2), 3.9 (s, 3H, CH3), 5.2 (s, 2H, CH2), 7.8 (s 1H, Ar), 7.9 (s, 1H, Ar), 8.2 (s, 1H, Ar); MS: m/e (ES+) 508 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]2[CH3:26])=[C:4]([F:28])[CH:3]=1.[N:29]([C:32]1[C:33]([CH3:38])=[N:34][O:35][C:36]=1[CH3:37])=[C:30]=[O:31]>>[CH3:38][C:33]1[C:32]([NH:29][C:30]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH2:9][N:10]3[C:14](=[O:15])[C:13]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]3[CH3:26])=[C:4]([F:28])[CH:3]=2)=[O:31])=[C:36]([CH3:37])[O:35][N:34]=1
Reactant: Cc1noc(C)c1N=C=O
Reactant: CCCC1(c2ccc(F)cc2)N=C(C)N(CC(=O)c2ccc(N)cc2F)C1=O
Product: CCCC1(c2ccc(F)cc2)N=C(C)N(CC(=O)c2ccc(NC(=O)Nc3c(C)noc3C)cc2F)C1=O

Procedure:
Synthesis in analogy to Example 7 and Example 10 starting from (+/−)-3-[2-(4-amino-2-fluoro-phenyl)-2-oxo-ethyl]-5-(4-fluoro-phenyl)-2-methyl-5-propyl-3,5-dihydro-imidazol-4-one and 4-isocyanato-3,5-dimethyl-isoxazole to yield (+/−)-1-(3,5-dimethyl-isoxazol-4-yl)-3-(3-fluoro-4-{2-[4-(4-fluoro-phenyl)-2-methyl-5-oxo-4-propyl-4,5-dihydro-imidazol-1-yl]-acetyl}-phenyl)-urea. The compound is suspended in a 1 molar aqueous sodium hydroxide solution. Subsequently iodomethane (1 equivalent) and tetrabutyl ammonium chloride (1 equivalent) are added and the mixture is stirred for 18 hours at room temperature. Subsequently the product is extracted with dichloromethane and subjected to preparative LC purification (method 3) to yield (+/−)-1-(3,5-dimethyl-isoxazol-4-yl)-3-(3-fluoro-4-{2-[4-(4-fluoro-phenyl)-2-methyl-5-oxo-4-propyl-4,5-dihydro-imidazol-1-yl]-acetyl}-phenyl)-1,3-dimethyl-urea LC/MS at 254 nm; [M+H] 552; Rt 3.502 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([N:17]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([S:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=3[F:42])[N:27]=2)[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:43][C@H:44]([CH2:47][CH3:48])[CH2:45][OH:46]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([N:17]([C:26]2[CH:31]=[C:30]([NH:43][C@@H:44]([CH2:45][OH:46])[CH2:47][CH3:48])[N:29]=[C:28]([S:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=3[F:42])[N:27]=2)[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:23])[CH3:24])(=[O:15])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)N(COCC[Si](C)(C)C)c2cc(Cl)nc(SCc3cccc(Cl)c3F)n2)CC1
Reactant: CC[C@@H](N)CO
Product: CC[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(Cl)c2F)n1
Temperature: 80 °C

Procedure:
The subtitle product of step i) (0.60 g) was diluted in (2R)-2-aminobutan-1-ol (2 ml) and heated at 80° C. for 18 h. The subtitle compound was recovered as a colourless oil by flash column chromatography (EtOAc/iso-hexane mixtures). Yield: 0.40 g.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=3[CH3:26])=[C:16]([F:27])[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.[C:28]([Si:30]([CH3:33])([CH3:32])[CH3:31])#[CH:29]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:29]#[C:28][Si:30]([CH3:33])([CH3:32])[CH3:31])=[CH:21][C:20]=3[CH3:26])=[C:16]([F:27])[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)NOCC2CC2)cc2[nH]cnc2c1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C#C[Si](C)(C)C)ccc1Nc1c(C(=O)NOCC2CC2)cc2[nH]cnc2c1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxy-amide 11ccc (0.025 g, 0.052 mmol) is dissolved in 1:1 acetonitrile/triethylamine (0.50 mL). Ethynyl-trimethylsilane (0.013 mL, 0.092 mmol), Pd(PPh3)2Cl2 (0.004 g, 0.006 mmol), and CuI (0.002 g, 0.011 mmol) are added consecutively and the reaction mixture is stirred at 60° C. for 1 hour under N2. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is purified by FCC (eluting with 20:1 methylene chloride:methanol) to yield 0.020 g (87%) of the desired product.
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:24]([C:26]([CH3:28])=[O:27])=[CH2:25]>CO>[O:27]=[C:26]([CH3:28])[CH2:24][CH2:25][N:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:25][CH2:24][C:26](=[O:27])[CH3:28])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC(C)=O
Reactant: c1ccc(CNCCCCCCCNCc2ccccc2)cc1
Solvent: CO
Product: CC(=O)CCN(CCCCCCCN(CCC(C)=O)Cc1ccccc1)Cc1ccccc1

Procedure:
Dissolve N,N'-bis[(phenyl)methyl]-1,7-heptanediamine (9.3 g, 0.03 mol) in methanol (120 ml) and while stirring the mixture introduce methyl vinyl ketone (5.6 ml, 0.066 mol) in a stream of nitrogen gas. Stir the mixture for 18 hours to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][N:15]([CH3:23])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:22][C:19]3[CH:20]=[CH:21][C:16]([N:15]([CH3:23])[CH3:14])=[CH:17][CH:18]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: CSc1ncnc2cc(N)ncc12
Product: CN(C)c1ccc(Nc2ncnc3cc(N)ncc23)cc1
Temperature: 190 °C
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (256 mg, 1.33 mmole) and N,N-dimethyl-1,4-phenylenediamine (1.95 g, 14.4 mmole) is stirred under N2 at 190° C. for 20 min. The resulting product is chromatographed over alumina (3-7k EtOH/CHCl3) to give 7-amino-4-(4-dimethylaminoanilino)pyrido[4,3-d]pyrimidine (198 mg, 53%) as an orange solid. 1H NMR (DMSO) δ 9.67 (1H, brs), 9.27 (1H, s), 8.27 (1H, s), 7.51 (2H, d, J=8.9 Hz), 6.75 (2H, d, J=8.9 Hz), 6.51 (2H, brs), 6.39 (1H, s), 2.89 (6H, s).
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([OH:16])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>CCO>[C:2]1([C:1]2[C:9]3[CH:13]=[CH:12][S:11][C:10]=3[C:14](=[O:16])[NH:18][N:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccccc1)c1ccsc1C(=O)O
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2ccccc2)c2ccsc12
Yield: 102.8 %

Procedure:
A solution of 3-benzoylthiophene-2-carboxylic acid (0.497 g, 2.14 mmol) (Alfa Aesar) and hydrazine hydrate (0.50 mL, 8.8 mmol) in EtOH (6 mL) was stirred at 85° C. for 4 hours, concentrated, and azeotroped with toluene to give the title compound (0.50 g, 2.2 mmol) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 8.28 (d, 1H), 7.69-7.75 (m, 2H), 7.51-7.59 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15](I)[CH:16]=[CH2:17]>CN(C=O)C.C(OCC)(=O)C>[CH2:17]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH:16]=[CH2:15]
Reactant: C=CCI
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1cccc(Br)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Bromophenol (10.0 g, 57.8 mmoles) in anhydrous DMF (60 mL) was treated with K2CO3 (24.0 g, 173 mmoles) and allyl iodide (5.81 mL, 63.6 mmoles). Reaction stirred overnight at 80° C. Reaction allowed to cool to room temperature and diluted with ethyl acetate. The mixture was washed with H2O (2×), brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to provide the title compound with no further purification.