Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@@H:28]1[CH3:33]>>[CH3:33][C@@H:28]1[N:27]([CH3:26])[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:29]1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: C[C@H]1CNCCN1C
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN(C)[C@@H](C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1,2-dimethylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (br. s., 3H) 2.33 (d, J=2.27 Hz, 3H) 2.84 (s, 3H) 3.13-3.74 (m, 7H) 7.63 (d, J=6.82 Hz, 1H) 7.71-7.78 (m, 1H) 7.90-8.67 (m, 4H). ESI-MS m/z [M+H]+ 435.3.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[N:7]=[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]=1[CH:13]=[O:14].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C:17]1=[O:25].N1CC[CH2:29][CH2:28][CH2:27]1>CC(O)C>[CH3:1][N:2]([CH3:15])[C:3]1[N:7]=[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]=1/[CH:13]=[C:18]1/[C:17](=[O:25])[NH:16][C:24]2[C:19]/1=[CH:20][CH:21]=[CH:22][CH:23]=2.[CH3:27][CH:28]([OH:14])[CH3:29]
Reactant: CN(C)c1nc2cccccc-2c1C=O
Reactant: O=C1Cc2ccccc2N1
Reactant: C1CCNCC1
Solvent: CC(C)O
Product: CN(C)c1nc2cccccc-2c1/C=C1/C(=O)Nc2ccccc21

Procedure:
20 mg (4Z,6Z,8E)-2-(dimethylamino)cyclohepta[b]pyrrole-3-carbaldehyde, 25 mg oxindole, and 0.1 mg piperidine were added in IPA with reflux for 20 hours. After cooling, red crystals were precipitated. After filtration and washing by IPA, Compound 035 was obtained (55%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH:18]([Li])(CC)C.C1CCCCC1.CN(C=O)C.[NH2:34][CH:35]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:42]1([CH:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:34]=[CH:18][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:9]3)=[CH:4][CH:3]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Brc1ccc2ccc(-c3ccccc3)nc2c1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: C(=NC(c1ccccc1)c1ccccc1)c1ccc2ccc(-c3ccccc3)nc2c1
Temperature: -50 °C
Reaction time: 0.08 h

Procedure:
7-Bromo-2-phenyl-quinoline (40.0 g, 0.141 mol) was added to a 1000 mL three-neck round bottom flask (rbf). The flask was degassed and filled with N2. THF (400 mL) was added. The solid dissolved. The flask was kept in a cooling bath (at −62° C.). The off-white solid crashed out at low temperature. 1.4 M of sec-butyllithium in cyclohexane (125.7 mL, 0.176 mol) was added within 15 min, and the internal temperature was kept at around −50° C. After addition was complete, the reaction was stirred at −50° C. (internal temperature) for 5 min. DMF (13.6 mL, 0.176 mol) was added within 10 min and the internal temperature was always kept at around −50° C. and the cooling bath was kept at around at −62° C. After 35 min, the reaction was quenched by NH4Cl/water (200 mL), and EtOAc (200 mL) was added. The organic layer was washed with water (300 mL×2) and brine (150 mL), dried over MgSO4, filtered and concentrated in vacuo. After evaporating to almost dryness, EtOAc (200 mL) was added and heated in a 70° C. oil bath to dissolve the solid. Half of the aminodiphenylmethane (26.2 mL, 0.148 mol) was added and the reaction was stirred at 58° C. (internal temperature) for 5 min. The reaction was seeded and the solid came out of solution slowly. After 5 min, the remaining aminodiphenylmethane was added within 3 min. The oil bath temperature was kept at 70° C., the internal temperature increased to 67° C. After 10 min, the reaction mixture was cooled in an ice bath. The off-white solid was collected by vacuum filtration and dried in vacuo at 40-60° C. for 2 hours. The title compound was isolated as an off-white solid (37.42 g, 67% yield).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C:14]3[S:15][C:16]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:17][CH:18]=3)=[O:13])=[CH:6][C:5]=12.CN1CCOCC1.[CH:32]([O:35][C:36](Cl)=[O:37])([CH3:34])[CH3:33]>ClCCl>[CH3:33][CH:32]([O:35][C:36]([N:22]1[CH2:23][CH2:24][CH:19]([C:16]2[S:15][C:14]([C:12](=[O:13])[NH:11][CH2:10][C:7]3[CH:8]=[CH:9][N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=3)=[CH:18][CH:17]=2)[CH2:20][CH2:21]1)=[O:37])[CH3:34]
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNCC2)s1
Reactant: CC(C)OC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(c2ccc(C(=O)NCc3ccn4ccnc4c3)s2)CC1

Procedure:
To a suspension N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-(piperidin-4-yl)thiophene-2-carboxamide (0.103 g, 0.249 mmol) in dichloromethane (2 ml) was added N-methylmorpholine (0.110 ml, 0.997 mmol) followed by isopropylchloroformate (0.374 ml, 0.374 mmol). A second portion of isopropylchloroformate (0.4 ml) was added and after 1 hour the mixture was directly purified by normal phase chromatography to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.05 (t, J=6.0 Hz, 1H), 8.51 (d, J=7.0 Hz, 1H), 7.92 (s, 1H), 7.68 (d, J=3.8 Hz, 1H), 7.56 (d, J=1.2 Hz, 1H), 7.40 (d, J=1.4 Hz, 1H), 6.96 (d, J=3.8 Hz, 1H), 6.88 (dd, J=7.0, 1.7 Hz, 1H), 4.78 (hept, J=6.2 Hz, 1H), 4.47 (d, J=5.9 Hz, 2H), 4.05 (d, J=12.9 Hz, 2H), 3.10-2.97 (m, 1H), 2.98-2.81 (m, 2H), 2.01-1.88 (m, 2H), 1.57-1.38 (m, 2H), 1.19 (d, J=6.2 Hz, 6H); MS (ESI(+)) m/e 427 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[C:13]1([CH:9]2[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]([F:33])([F:32])[F:21])=[CH:3][CH:4]=3)[CH2:8]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Brc1ccc(CN2CCCC(c3ccccc3)C2)cc1
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: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCCC(c3ccccc3)C2)cc1
Temperature: 120 °C
Yield: 100 %

Procedure:
100 mg of 1-(4-Bromo-benzyl)-3-phenyl-piperidine was combined with 862 mg of 2-(Trifluoromethyl)phenyl boronic acid, 35 mg of tetrakis(triphenylphosphine)palladium(0), 1.015 mL of 2M sodium carbonate solution, 2.7 mL toluene and 1.4 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by reverse phase HPLC. ES MS (+) m/z 396, 100% yield
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:11])[N:4](C)[C:5](=[O:9])[NH:6][C:7]=1Cl.[CH3:12][N:13]=[C:14]=[S:15].O.[CH3:17][N:18](C)C=O>>[CH3:12][NH:13][C:14]([NH:18][CH2:17][C:7]1[NH:6][C:5](=[O:9])[NH:4][C:3](=[O:11])[C:2]=1[Cl:1])=[S:15]
Reactant: Cn1c(=O)[nH]c(Cl)c(Cl)c1=O
Reactant: CN=C=S
Reactant: CN(C)C=O
Solvent: O
Product: CNC(=S)NCc1[nH]c(=O)[nH]c(=O)c1Cl
Temperature: 70 °C
Yield: 61 %

Procedure:
A suspension of 0.50 g of 5-chloro-6-chloro-methyluracil and 0.22 g of methyl isothiocyanate in N,N-dimethylformamide (3 ml) was heated at 70° C. for 4 hours under stirring. Water (50 ml) was added to the reaction mixture. A crystallized matter was collected by filtration and then washed with water and methanol, whereby 435 mg of the title compound were obtained (yield: 61%).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C(N(CC)CC)C.S([Cl:27])(C)(=O)=O.S([O-])(=O)(=O)C>C(Cl)Cl.O>[Cl:27][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCN1CCN(c2ccccc2)CC1
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: ClCCN1CCN(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
The crude 1-(2-hydroxyethyl)-4-phenylpiperazine (~400 g) thus obtained was dissolved in dry CH2Cl2 (3.5 l) containing triethylamine (400 ml; 2.9 mol) and the solution was cooled to -10°. A solution of 250 g (2.18 mol) mesyl chloride in 300 ml CH2Cl2 was added to the stirred mixture over 30 min and then the reaction was allowed to warm up to room temp. It was then stirred at ambient temperature until the in situ conversion of the intermediate mesylate to the chloro compound was completed (16-40 hrs). Water (1 l) was added and the layers separated. The aqueous layer was washed with CH2Cl2 (1×300 ml) and then the combined CH2Cl2 phases were dried (K2CO3) and evaporated. The residue was triturated with hot hexane (1×1 l; 4×200 ml) and the combined extracts were decolorized (charcoal) and then cooled to 0° -5°. Filtration of the resulting colorless crystals afforded 1-(2-chloroethyl)-4-phenylpiperazine, mp 56°-58°. Concentration of the mother liquor to ~400 ml furnished additional product, mp 55°57°.
Reaction SMILES: [F:1][C:2]1[C:3]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH:13]4[CH2:17][NH:16][CH2:15][CH:14]4[CH:18]=3)[NH:8][C:5]2=[N:6][CH:7]=1.Cl[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31].C(N(CC)CC)C.O>CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]1[C:3]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:12][CH:13]4[CH2:17][N:16]([CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:15][CH:14]4[CH:18]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CC4CNCC4C3)cc12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CC4CN(CC(=O)N(C)C)CC4C3)cc12

Procedure:
A mixture of Example 282A (80.0 mg, 0.182 mmol), 2-chloro-N,N-dimethylacetamide (0.021 mL, 0.209 mmol), and triethylamine (0.127 mL, 0.908 mmol) in N,N-dimethylformamide (2 mL) was heated at 75° C. for 4 hours. The mixture was treated with water and brine and extracted with ethyl acetate (twice). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, concentrated, and purified by HPLC (same protocol as Example 221). The trifluoroacetic acid salt was flushed through an SCX column eluting with 2M ammonia in methanol to give the free base of the title compound. 1H NMR (400 MHz, Pyridine-d5) δ 2.58-3.06 (m, 13H), 3.31 (d, J=5.4 Hz, 2H), 3.39-3.44 (m, 1H), 3.71 (s, 3H), 6.43 (bs, 1H), 6.48 (bs, 1H), 7.12 (dd, J=9.1, 4.5 Hz, 1H), 7.27-7.36 (m, 1H), 7.50 (d, J=8.8 Hz, 1H), 8.51 (d, J=2.6 Hz, 1H), 13.13 (bs, 1H). MS (ESI+) m/z 453.2 (M+H)+.
Reaction SMILES: [C:1]1([N:7]=[C:8]([S:15][CH:16]([CH3:22])[CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:9]#[C:10][Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]1[CH:35]=[CH:34][C:33]([SH:36])=[CH:32][CH:31]=1>CO>[F:29][C:30]1[CH:35]=[CH:34][C:33]([S:36][CH:10]=[CH:9][C:8](=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:15][CH:16]([CH3:22])[CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:32][CH:31]=1
Reactant: CCC(CC)C(C)SC(C#C[Si](C)(C)C)=Nc1ccccc1
Reactant: Fc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCC(CC)C(C)SC(C=CSc1ccc(F)cc1)=Nc1ccccc1
Reaction time: 1 h

Procedure:
Etynyltrimethylsilane (0.7 mL) was dissolved to dry THF (15 mL), hexane solution of n-butyl lithium (1.58 moL/L; 3.2 mL) was added dropwise to the solution at −78° C., and then the mixture was allowed to warm to 0° C. After that, THF (2 mL) solution of phenyl isotiocyanate (0.61 mL) was added dropwise to the mixture, and then it was stirred for 30 minutes under ice-cooling. THF (1 mL) solution of 2-ethyl-1-methylbutyl methanesulfonate (1.01 g) was added to the solution and heated under reflux for 6.5 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to Florisil column chromatography(hexane/ethyl acetate=20/1) to obtain 2-ethyl-1-methylbutyl N-phenyl-3-(trimethylsilyl)thiopropynimidate (0.74 g). Obtained 2-ethyl-1-methylbutyl N-phenyl-3-(trimethylsilyl)thiopropynimidate was dissolved to methanol (15 mL), and then small amount of potassium carbonate was added to the solution at room temperature, and then it was stirred for 1 hour. After that, 4-fluorothiophenol (0.19 mL) was added to the mixture at room temperature and stirred for 2.7 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane/ethyl acetate=20/1) and medium pressure HPLC (hexane/ethyl acetate=99/1) to obtain 2-ethyl-1-methylbutyl 3-(4-fluorophenylthio)-N-(phenyl)thioacrylimidate (0.43 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[N:3]=1>C(N)CN.C(OCC)(=O)C>[ClH:1].[NH2:3][CH2:4][CH2:5][NH:6][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[N:3]=1
Reactant: CCn1cnc2c(Nc3cccc(C#N)c3)nc(Cl)nc21
Solvent: CCOC(C)=O
Solvent: NCCN
Product: CCn1cnc2c(Nc3cccc(C#N)c3)nc(NCCN)nc21
Product: Cl

Procedure:
0.2 g (0.6 mmol) of 2-chloro-9-ethyl-6-(3-cyano-phenyl-amino)-9H-purine is stirred in 2.5 ml of ethylenediamine at 75° C. for 3.5 h, and the mixture is allowed to cool and is diluted with ethyl acetate. The organic phase is washed with water, separated off and dried over sodium sulfate. After removal of the solvent, the residue is dissolved in 3 ml of dioxane and treated with 4 N HCl in dioxane. 2-(2-Amino-ethyl-amino)-6-(3-cyano-phenyl-amino)-9-ethyl-9H-purine hydrochloride is obtained as a crystalline precipitate. This is filtered off and dried; m.p. 200° C.; FAB-MS: (M+H)+=323; Rf=0.5 (ethyl acetate:i-propanol:water: 22% aqueous ammonium hydroxide solution=40:60:15:10).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:25]([C:33]2[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][N:34]=2)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]3([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)[CH:7]=1.[N:43]([CH:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)=[C:44]=[O:45].NC(N)=O.[N-]=C=O>C1COCC1.C(OCC)(=O)C.CCN(CC)CC>[Si:18]([O:17][C:13]1([C:11]2[S:12][C:8]([C:6]3[CH:5]=[C:4]([N:25]([C:33]4[N:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:35][N:34]=4)[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:31])[CH3:29])[CH:3]=[C:2]([NH:1][C:44](=[O:45])[NH:43][CH:46]4[CH2:50][CH2:49][CH2:48][CH2:47]4)[CH:7]=3)=[CH:9][N:10]=2)[CH2:14][CH2:15][CH2:16]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N(c1cc(N)cc(-c2cnc(C3(O[Si](C)(C)C(C)(C)C)CCC3)s2)c1)c1nccc(C(F)(F)F)n1
Reactant: O=C=NC1CCCC1
Agent: NC(N)=O
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1cc(NC(=O)NC2CCCC2)cc(-c2cnc(C3(O[Si](C)(C)C(C)(C)C)CCC3)s2)c1)c1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of the product of Step 2 (56 mg; 0.090 mmol) in THF (0.9 mL) was added triethylamine (38 μL; 0.27 mmol) followed by the isocyanatocyclopentane (31 μL; 0.27 mmol), then the mixture was stirred at room temperature overnight, at which point LC-UV analysis indicated ˜70% conversion to the desired urea. Additional Et3N and isocyanate (0.27 mmol each) were added, and the mixture was heated to 50° C. for 3 hours, at which point LC-UV indicated complete conversion. The mixture was diluted with ethyl acetate (30 mL) and washed with water (30 mL) and brine (30 mL). The organic extracts were dried (Na2SO4) and concentrated in vacuo. Purification by chromatography on silica gel (90:10 to 40:60, hexanes:ethyl acetate) provided 57 mg (0.078 mmol, 86%) of tert-butyl {3-[2-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclobutyl)-1,3-thiazol-5-yl]-5-[(cyclopentylcarbamoyl)amino]phenyl}[4-(trifluoromethyl)pyrimidin-2-yl]carbamate as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[CH2:45]([N:52]1[CH2:57][CH2:56][CH:55]([NH2:58])[CH2:54][CH2:53]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(Cl)(Cl)Cl.O>[CH2:45]([N:52]1[CH2:57][CH2:56][CH:55]([NH:58][C:37]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][C:18]=2[N+:23]([O-:25])=[O:24])=[O:43])[CH2:54][CH2:53]1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCN(Cc5ccccc5)CC4)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-nitroaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (131 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 1-benzyl-4-piperidineamine (84 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (141 mg, yield 86%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]2[C:16]([I:17])=[CH:15][NH:14][C:10]=2[N:11]=[CH:12][N:13]=1.Br[CH2:19][CH:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:21]=[CH2:22].O>CN(C=O)C.C(OCC)(=O)C>[Si:24]([O:23][CH:20]([CH:21]=[CH2:22])[CH2:19][N:14]1[C:10]2[N:11]=[CH:12][N:13]=[C:8]([Cl:7])[C:9]=2[C:16]([I:17])=[CH:15]1)([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:25])[CH3:26]
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: C=CC(CBr)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(Cn1cc(I)c2c(Cl)ncnc21)O[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Reaction time: 5 h
Yield: 36.8 %

Procedure:
Potassium carbonate (2.2 g) was added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (3.7 g) obtained in Step 1 and 1-bromo-2-(tert-butyldimethylsilyloxy)-3-butene (3.5 g) obtained in Step 2 in DMF (26 ml) at room temperature, and the mixture was stirred at 80° C. for 5 hours. After cooling the reaction mixture, water and ethyl acetate were added thereto, and the generated insoluble matter was filtered off. The organic layer was separated, washed with water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow solid (2.25 g).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[N:16]([CH:17]=1)[CH2:15][CH2:14][O:13][C:12]1[C:7]2=[CH:8][C:9]([C:19]#[C:20][C:21]([OH:27])([CH3:26])[C:22]([O:24]C)=O)=[C:10]([F:18])[CH:11]=1)(=[O:3])[NH2:2].[CH:28]1([NH2:31])[CH2:30][CH2:29]1>CO>[CH:28]1([NH:31][C:22]([C:21]([OH:27])([CH3:26])[C:20]#[C:19][C:9]2[C:10]([F:18])=[CH:11][C:12]3[O:13][CH2:14][CH2:15][N:16]4[C:6](=[N:5][C:4]([C:1]([NH2:2])=[O:3])=[CH:17]4)[C:7]=3[CH:8]=2)=[O:24])[CH2:30][CH2:29]1
Reactant: COC(=O)C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Reactant: NC1CC1
Solvent: CO
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)C(=O)NC1CC1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
Into a 8-mL vial, was placed a solution of methyl 4-[4-carbamoyl-12-fluoro-9-oxa-3,6-diazatricyclo[8.4.0.0[2,6]]tetradeca-1(14),2,4,10,12-pentaen-13-yl]-2-hydroxy-2-methylbut-3-ynoate (120 mg, 0.32 mmol, 1.00 equiv) and cyclopropanamine (1.83 g, 32.05 mmol, 99.72 equiv) in methanol (2 mL). The resulting solution was stirred for 12 h at 40° C. in an oil bath and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (30:1). This resulted in 23 mg (18%) of 9-(3-Cyclopropylcarbamoyl-3-hydroxy-but-1-ynyl)-8-fluoro-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a yellow solid. LC-MS: (ES, m/z): 399 [M+H]+; 1H-NMR: (300 MHz, DMSO-d6, ppm): δ 8.558 (d, 1H), 7.892 (d, 1H), 7.782 (s, 1H), 7.575 (br s, 1H), 7.126 (br s, 1H), 7.023 (d, 1H), 6.510 (s, 1H), 4.600-4.400 (m, 4H), 2.800-2.600 (m, 1H), 1.600 (s, 3H), 0.633-0565 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][NH:6][C:5](=[O:8])[CH2:4]1.[H-].[Na+].Cl[C:12]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:24]([C:35]([F:38])([F:37])[F:36])[CH:23]=2)[CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2>>[O:32]1[CH2:33][CH2:34][CH:29]([O:28][C:25]2[CH:26]=[CH:27][C:22]([C:20]3[CH:19]=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[N:17]4)=[C:12]([O:1][CH2:2][C@H:3]4[CH2:7][NH:6][C:5](=[O:8])[CH2:4]4)[N:21]=3)=[CH:23][C:24]=2[C:35]([F:38])([F:37])[F:36])[CH2:30][CH2:31]1
Reactant: FC(F)(F)c1cc(-c2cc3ncccc3c(Cl)n2)ccc1OC1CCOCC1
Reactant: O=C1C[C@@H](CO)CN1
Agent: [H-]
Agent: [Na+]
Product: O=C1C[C@@H](COc2nc(-c3ccc(OC4CCOCC4)c(C(F)(F)F)c3)cc3ncccc23)CN1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
50.7 mg (R)-4-Hydroxymethyl-pyrrolidine-2-one (2.2) was placed in 1.5 mL of dimethylacetamaide at ambient temperature under nitrogen before 20.5 mg sodium hydride (60% dispersion in oil) was added. The reaction was stirred for 10 min and then 150 mg 5-chloro-7-[4-(tetrahydro-pyran-4-yloxy)-3-trifluoromethyl-phenyl]-[1,6]naphthyridine (6.23) was introduced and the reaction was heated to 70° C. and stirred overnight. After this time the mixture was cooled to ambient temperature and partitioned between ethyl acetate, water and some saturared sodium chloride solution. The organic layer was separated, dried over sodium sulfate, filtered and the solvent was removed from the filtrate under reduced pressure. Purification by chromatography on silica provided the title compound.