Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14](=[CH2:21])[CH2:13][CH2:12][NH:11][CH2:10][C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>ClCCl>[CH2:1]([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14](=[CH2:21])[CH2:13][CH2:12][N:11]([C:31](=[O:32])[NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=2)[CH2:10][C:9]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: C=C1CCNCC(=O)N(Cc2ccccc2)c2ccccc21
Solvent: ClCCl
Product: C=C1CCN(C(=O)Nc2cccc(C)c2)CC(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
A solution of 1-benzyl-7-methylene-2-oxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine (94 mg, 0.32 mmol) and 3-methylphenylisocyanate (42 μl, 0.33 mmol) was stirred in dichloromethane (2 ml) at room temperature for 3 hours. Evaporation of the solvent and chromatography on silica gel with ethyl acetate-hexane as eluant (1:1) gave the product. (131 mg, 96%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[F:39][C:40]1[CH:41]=[C:42]([CH:44]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:46]=1)[NH2:43].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:43][C:42]1[CH:44]=[C:45]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:46]=[C:40]([F:39])[CH:41]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(N)cc(F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc(F)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 53 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (250 mg, 0.42 mmol) was treated with 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (250 mg, 1.05 mmol), sodium carbonate (110 mg, 1.05 mmol) and 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (100 mg, 0.12 mmol) in a mixture of 1,2-dimethoxyethane (10.6 ml) and water (2.4 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 70% n-hexane-ethyl acetate) to obtain 170 mg (53% yield, 82% purity) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl.[CH3:28][O:29][CH2:30][CH2:31][NH:32][C:33]([C@H:35]1[CH2:40][CH2:39][C@H:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34]>>[CH3:28][O:29][CH2:30][CH2:31][NH:32][C:33]([C@H:35]1[CH2:36][CH2:37][C@H:38]([NH:41][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:39][CH2:40]1)=[O:34]
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: COCCNC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: COCCNC(=O)[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and trans-4-amino-cyclohexanecarboxylic acid (2-methoxy-ethyl)-amide hydrochloride (A196) the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Li+].CCC[CH2-].[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([B:18]([OH:23])[OH:19])=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-n2cccn2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: OB(O)c1ccnn1-c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a stirred solution of commercially available 1-(4-fluorophenyl)-1H-pyrazole [CAS No 81329-32-0] (1.6 g, 9.87 mmol) in THF (39.5 ml) was added drop wise at −78° C. under nitrogen atmosphere N-butyllithium (1.6 N in hexane, 6.47 ml, 10.4 mmol). After the mixture was allowed to stir at −78° C. for 1 h triisopropyl borate (7.65 g, 9.35 ml, 39.5 mmol) was added at −78° C. The mixture was allowed to stir at −78° C. for 1 h, gradually warmed to room temperature, and the pH of the mixture was adjusted to 5 with 1 M HCl solution. The mixture was evaporated and the remaining water layer extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (30 ml), dried over MgSO4 and evaporated. The raw product was purified by column chromatography on silica gel (dichloromethane/MeOH) and trituration (diethyl ether/hexane) to yield the title compound as a white solid (479 mg, 24%), MS (ISN) m/z=205.0 [(M−H)−], mp 115° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12](=[O:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(O)C.[Cl-].[NH4+].C(=O)([O-])[O-].[K+].[K+]>[Fe].O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:11][C:12](=[O:21])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=O)C=Cc1ccccn1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)cc1NC(=O)/C=C/c1ccccn1
Temperature: 70 °C

Procedure:
8.6 g of the product of step 2 was added to 200 ml ethanol:water (v/v=3/1), then 13.6 g of iron powder and 5.0 g of ammonium chloride were added. After addition, the reaction mixture was heated to 70° C., and reacted for 30 min. The completion of reaction was indicated by TLC. Then the reaction mixture was filtered, washed with hot ethanol repeatedly, and concentrated under reduced pressure to give a yellow solid. 20 ml of potassium carbonate solution (10%) was added to the solid. The mixture was stirred, left to stand, filtered, and dried to give a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9](OCC)=[O:10])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1([CH2:9][OH:10])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1
Solvent: ClCCl
Product: CCOC(=O)C1(CO)CC1

Procedure:
In accordance with the method described in the document (Tetrahedron Letters, 40, 5467 (1988)), a solution of 720 mg of 1-hydroxymethyl-cyclopropane carboxylic acid ethyl ester obtained from 1,1-cyclopropane dicarboxylic acid diethyl ester in 10 mL of dichloromethane was added with 1.05 mL of triethylamine and 0.5 mL of methanesulfonyl chloride under ice cooling, and stirred at this temperature for 2 hours. After adding water, the reaction solution was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated brine, saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, to afford 1.04 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+:44]1[C:52]2[C:47](=NC=C[CH:51]=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.C(N)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:44][CH:52]([CH3:47])[CH3:51])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)NC(C)C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 90.1 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.30 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.009 g (0.15 mmole) isopropylamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient a 0:100-80:20) to give 0.044 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-isopropyl-3-methoxy-benzamide (I-25) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([Cl:10])[CH:3]=1.CON(C)[C:14](=[O:28])[C@@H:15]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:16].C(=O)=O.CC(C)=O.N#N.Cl>C1COCC1.[Cl-].[Na+].O>[Cl:10][C:4]1[CH:3]=[C:2]([C:14](=[O:28])[C@@H:15]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:16])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Reactant: COc1ccc(Br)cc1Cl
Agent: Cl
Agent: N#N
Agent: O=C=O
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)[C@H](C)NC(=O)OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.4 %

Procedure:
A solution of 4-bromo-2-chloroanisole (3 g, 13.55 mmol) and (S)-benzyl (1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (3.79 g, 14.22 mmol) in THF (33.9 mL) was cooled to −20° C. with dry ice/acetone. To this solution was added isopropylmagnesium chloride lithium chloride complex (22.9 mL, 29.8 mmol) at −20° C. dropwise under N2. After addition, the reaction mixture was warmed up to rt and stirred overnight. The reaction mixture was cooled to −40° C. and slowly poured into a stirred mixture of crushed ice and 30 mL of 1N HCl. The resulting mixture was diluted with 30 mL of brine, extracted with EtOAc (3×50 mL). The organic layer was dried with Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluted with 0-100% EtOAc in hexane to give (S)-benzyl (1-(3-chloro-4-methoxyphenyl)-1-oxopropan-2-yl)carbamate (0.82 g) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.05 (s, 1H), 7.92 (d, 1H), 6.98 (d, 1H), 5.93 (d, 1H), 5.29 (m, 1H), 5.16 (s, 2H), 3.99 (s, 3H), 1.43 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[N:32]1[N:33]([C:37]2[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=2[C:39](O)=[O:40])[N:34]=[CH:35][CH:36]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][N:13]([C:39]([C:38]4[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=4[N:33]4[N:34]=[CH:35][CH:36]=[N:32]4)=[O:40])[CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1cnc(N2C[C@@H]3CCNC[C@@H]32)cn1
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1cnc(N2C[C@@H]3CCN(C(=O)c4ccccc4-n4nccn4)C[C@@H]32)cn1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(5-methylpyrazin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 29) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 14) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C20H21N7O, 375.44; m/z found 376.0 [M+H]+. 1H NMR (CDCl3): 8.06-7.78 (m, 3H), 7.72-7.44 (m, 3H), 7.39-7.28 (m, 1H), 7.16-6.96 (m, 1H), 4.56-3.98 (m, 4H), 3.80-2.96 (m, 4H), 2.46-2.03 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16](N(CC)CC)[CH3:17].ClC(OCC)=O.CN(C1C=CC=CN=1)C>O1CCCC1.C(O)C>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9]1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: CCOC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (28) (1.0 g, 0.0046 mol) and triethylamine (0.78 mL, 0.0056 mol) were dissolved in 20 mL tetrahydrofuran and cooled over ice water. Ethyl chloroformate (0.48 mL, 0.0051 mol) was added dropwise at 0-5° C. and the reaction was stirred for 30 minutes. A catalytic amount of dimethylaminopyridine was added followed by 5 mL ethanol and the mixture was warmed to room temperature and stirred for 1 hour. The mixture was concentrated and partitioned between water (50 mL) and ethyl acetate (1×100 mL). The aqueous layer was extracted with an additional 50 mL ethyl acetate. The combined organics were washed with 1×50 mL water, 1×25 mL saturated sodium chloride, and dried over Na2SO4. The dried organics were evaporated to an oil. The residue was chromatographed with 10 g silica gel, 20% ethyl acetate/hexanes, to obtain 0.92 g of clear colorless oil. MS (ESI) m/z 282 [M+K]+. NMR (CDCl3) δ 1.25-1.31 (t, 3H), 1.49 (s, 9H), 1.57 (s, 2H), 3.01-3.07 (m, 1H), 3.30-3.36 (m, 1H), 3.47-3.65 (m, 3H), 4.13-4.20 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[C:3]([NH:5][CH2:6][CH2:7][C:8]([OH:10])=O)=[O:4].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:45][CH2:46][CH2:47][O:48][C:49](=[O:66])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[NH:57][C:58]1[C:63]([Cl:64])=[CH:62][CH:61]=[CH:60][C:59]=1[Cl:65]>CN(C=O)C.O>[OH:1][C@H:2]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:45][CH2:46][CH2:47][O:48][C:49](=[O:66])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[NH:57][C:58]1[C:63]([Cl:64])=[CH:62][CH:61]=[CH:60][C:59]=1[Cl:65])=[O:10])=[O:4]
Reactant: NCCOC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)NCCOC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.4 %

Procedure:
To a stirred solution of 3-((R)-2,4-Dihydroxy-3,3-dimethyl-butyrylamino)-propionic acid 6 (0.2 g, 0.0007 mol, 1 eq) in DMF (4 mL) was added triethyl amine (0.31 g, 0.003 mol), EDC.HCl (0.22 g, 0.001 mol), HOBt (0.15 g, 0.001 mol) and [2-(2,6-Dichloro-phenylamino)-phenyl]-acetic acid 2-amino-ethyl ester 5 (0.26 g, 0.0007 mol, 1 eq) at rt. The resulting mixture was stirred at room temperature for 16 h. Reaction was monitored by TLC. After completion, reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). Combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure and purified by silica gel column chromatography using Methanol and DCM (3:97) to get 0.11 g (26.4% Yield) of CLX-SYN-G18-C01 as an off white solid; Mass: 539.9 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[CH3:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]1[N:33]=[CH:34][N:35]=[CH:36][C:27]2=1.CCN(C(C)C)C(C)C>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([CH3:16])=[C:18]([C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28]3[N:33]=[CH:34][N:35]=[CH:36][C:27]4=3)[CH:19]=2)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: Cc1ccc(N)cc1-c1ccc2[nH]c3ncncc3c2c1
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)Nc2ccc(C)c(-c3ccc4[nH]c5ncncc5c4c3)c2)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
To 4-methoxy-3-(trifluoromethyl)benzoyl chloride (11.0 μL, 0.070 mmol) was added a solution of 4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)aniline (17.5 mg, 0.064 mmol) and DIPEA (16 μL, 0.089 mmol) in tetrahydrofuran (THF) (0.4 mL). The reaction was stirred at ambient temperature until LCMS indicated complete reaction, typically 16 hours. The reaction mixture was diluted to a total of 2 mL with THF and MeOH and purified by preparative LCMS to recover the product as a TFA salt (18.6 mg, 49.4%). 1H NMR (300 MHz, DMSO): δ 13.0 (bs, 1H), 10.33 (s, 1H), 9.64 (s, 1H), 9.13 (s, 1H), 8.35 (s, 1H), 8.24 (m, 2H), 7.7-7.8 (m, 3H), 7.63 (dd, 1H), 7.41 (d, 1H), 7.32 (d, 1H), 2.25 (s, 3H). MS (EI) m/z=477 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[C:24]=1[CH2:25]Br>ClC(Cl)C>[Br:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([CH2:25][C:24]2[C:27]([C:31]([F:32])([F:34])[F:33])=[CH:28][CH:29]=[CH:30][C:23]=2[F:22])[CH:7]=1
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Reactant: Fc1cccc(C(F)(F)F)c1CBr
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CC(Cl)Cl
Product: O=c1[nH]c(=O)n(Cc2c(F)cccc2C(F)(F)F)cc1Br
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A suspension of 5-bromouracil (31.0 g) in 300 mL of dichloroethane is treated with N,O-bis(trimethylsilyl)acetamide (80 mL). The reaction mixture is heated under nitrogen. The solution is cooled to ambient temperature, 2-fluoro-6-(trifluoromethyl)benzyl bromide (50 g) is added and the reaction mixture is heated overnight under the nitrogen. The reaction is cooled, quenched with MeOH, and partitioned between dichloromethane and water. The organic layer is washed with brine, dried (sodium sulfate), and evaporated to give a solid. The crude product is triturated with ether, filtered, and washed with ether three times providing 40.7 g of 5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]pyrimidine-2,4(1H,3H)-dione 1a. MS (CI) m/z 366.0, 368.0 (MH+).
Reaction SMILES: [OH:1][C:2]([CH:11]=[CH2:12])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3]/[CH:4]=[CH:5]/[I:6].N1C=CN=C1.Cl[Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[CH3:20][Si:19]([CH3:22])([CH3:21])[O:1][C:2]([CH:11]=[CH2:12])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3]/[CH:4]=[CH:5]/[I:6]
Reactant: C=CC(O)(C/C=C/I)CCCC
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CC(C/C=C/I)(CCCC)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a stirred solution of 456 mg of 4-hydroxy-4-vinyl-1-iodo-trans-1-octene and 320 mg of imidazole in 1.0 ml of dimethylformamide is added 0.23 ml of chlorotrimethylsilane during 3 minutes. The mixture is stirred at room temperature for 22 hours and partitioned with a mixture of cold hexane and water. The hexane layer is washed repeatedly with water and then brine, dried over magnesium sulfate, and concentrated to give an oil, pmr spectrum (CDCl3): 0.13 (s, trimethylsiloxy group) and 2.32 (d, =CHCH2).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:18][CH2:19][N:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.CO.C(Cl)Cl>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][N:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]1=2
Reactant: O=C1CCCc2cc([N+](=O)[O-])ccc2N1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)CCN1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
A suspension of 7-nitro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (490 mg, 2.38 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (685 mg, 4.75 mmol) and potassium carbonate (1.97 g, 14.28 mmol) in 15 mL DMF was stirred at room temperature for 1 day. A TLC analysis indicated that the starting material was still present. The mixture was treated with 2-chloro-N,N-dimethylethanamine hydrochloride (685 mg, 4.75 mmol) and potassium carbonate (1.97 g, 14.28 mmol) followed by 5 mL DMF and stirring was continued at room temperature for 18 hours. After this time, the mixture was poured into 50 mL H2O, then extracted with 2×100 mL EtOAc. The combined organic fractions were washed with brine, dried over Na2SO4, filtered, and concentrated to give a dark residue. The residue was subjected to flash chromatography on silica gel using 2-5% 2M NH3 in MeOH/CH2Cl2 to give a yellow viscous oil (412 mg, 62.4%). 1H-NMR (DMSO-d6) δ 8.21-8.15 (m, 2H), 7.67 (d, J=8.7 Hz, 1H), 3.92-3.90 (m, 2H), 2.87-2.83 (m, 2H), 2.27 (t, J=6.3 Hz, 2H), 2.21-2.11 (m, 4H), 2.03 (s, 6H). MS (EI): 278.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[C:4]([C:11]([OH:13])=O)=[CH:3]1.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)Cl.C(OC(=O)C)C.CN(C=O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[NH:20][C:11]([C:4]2[C:5]([C:7]([F:10])([F:9])[F:8])=[CH:6][N:2]([CH3:1])[CH:3]=2)=[O:13])=[CH:32][CH:31]=1
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)c1
Reactant: Nc1cnccc1-c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2cnccc2-c2ccc(Cl)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.54 g (2.8 mmol) 1-methyl-4-trifluoromethylpyrrole-3-carboxylic acid and 0.39 g (3.1 mmol) oxalyl chloride in 20 ml methylene chloride is stirred for 2 hours at room temperature in the presence of a catalytic amount of DMF. Then the acid chloride solution is slowly added to a solution of 0.57 g (2.8 mmol) 3-amino4-(4′-chlorophenyl)pyridine, 0.34 g (3.4 mmol) triethylamine and 15 ml methylene chloride. The resulting mixture is then stirred for 16 hours at room temperature. After the addition of ethylacetate, the organic phase is washed twice with water. After drying the organic phase over sodium sulfate, the solvent is removed in a water let vacuum. The obtained crude product is purified by column chromatography over silica gel (eluant: hexane/THF 1:3). Yield: 0.4 g 1-methyl-4-trifluoromethyl-1-1-pyrrole-3-carboxylic acid [4-(4′-chlorophenyl)pyridin-3yl]amide in the form of yellowish crystals; m.p.: 178-180° C.