Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10](=O)[N:11]=1)=[N:8][C:7]([CH3:13])=[C:6]([CH3:14])[N:5]=2.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][NH2:23])=[CH:19][CH:18]=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C(Cl)Cl>C[Si](C)(C)N[Si](C)(C)C.O>[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][NH:23][C:10]2[C:9]3[C:4](=[N:5][C:6]([CH3:14])=[C:7]([CH3:13])[N:8]=3)[N:3]=[C:2]([CH3:1])[N:11]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(CCN)cc1
Reactant: Cc1nc(=O)c2nc(C)c(C)nc2[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CCNc2nc(C)nc3nc(C)c(C)nc23)cc1
Temperature: 115 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2,6,7-trimethylpteridin-4(1H)-one (1.1 g, 6.0 mmol), 4-methoxyphenethylamine (1.6 g, 11 mmol) and ammonium sulfate (0.56 g, 4.2 mmol) in hexamethyldisilazane (16 mL) was heated at 115° C. for 6 h. After cooling, the majority of solids were dissolved by addition of CH2Cl2 and H2O and the solvents removed in vacuo. The residue was slurried in a mixture of MeOH (5 mL) and H2O (50 mL) and stirred for 45 min. The bronze solid was collected by suction filtration and dried in vacuo at 50° C. The residue was dissolved in MeOH/CH2Cl2 and diluted with Et2O, causing crystallization. All solvent was allowed to evaporate, and the remaining solid dried in vacuo to afford [2-(4-methoxyphenyl)-ethyl]-(2,6,7-trimethylpteridin-4-yl)-amine as a brown powder (1.3 g; 67%): 1H NMR (300 MHz, CDCl3) δ 7.22-7.14 (m, 2H), 6.95 (t, J=6.3 Hz, 1H), 6.90-6.83 (m, 2H), 3.87 (dd, J=13.5, 6.8 Hz, 2H), 3.80 (s, 3H), 2.97 (t, J=7.2 Hz, 2H), 2.69 (s, 3H), 2.66 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: CO[C:3]([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)[N:8]=[C:7]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:6]=1)=[O:4].[CH2:34]([CH2:36][NH2:37])[OH:35]>CO>[OH:35][CH2:34][CH2:36][NH:37][C:3]([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)[N:8]=[C:7]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Reactant: NCCO
Solvent: CO
Product: Cc1cc(Nc2cc(C(=O)NCCO)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 88 °C
Yield: 51.6 %

Procedure:
A mixture of 6-methoxycarbonyl-4-(5-methyl-1H-pyrazol-3-ylamino)-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}pyrimidine (Example 45) (49.5 mg, 0.11 mmol) and ethanolamine (2.0 ml, 33.7 mmol) in methanol (4 ml) was heated at 88° C. for 2 hours. The volatiles were removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water/acetonitrile/TFA (95:5:0.2 decreasing in polarity to 0:100:0.2) the fractions containing product were combined and passed through a 50 g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutral impurities, followed by 7M methanolic ammonia to elute the product. The solvent was removed by evaporation, the residue triturated with diethylether and the resulting solid collected by filtration to give the title compound (27 mg, 57%).
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].[Si:25]([O:32][CH2:33][CH:34]=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].C([BH3-])#N.[Na+].O>CO>[Si:25]([O:32][CH2:33][CH2:34][N:16]1[CH2:17][CH2:18][CH:14]([CH2:13][N:9]2[C:10]3[C:5](=[CH:4][C:3]([I:2])=[CH:12][CH:11]=3)[C:6](=[O:24])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8]2)[CH2:15]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CCOC(=O)c1cn(CC2CCNC2)c2ccc(I)cc2c1=O
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1cn(CC2CCN(CCO[Si](C)(C)C(C)(C)C)C2)c2ccc(I)cc2c1=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 40.1 %

Procedure:
Ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 126, 500 mg, 1.08 mmol) was suspended in methanol (15 mL) then (tert-butyldimethylsilyloxy)acetaldehyde (1 mL, 5.4 mmol) and sodium cyanoborohydride (612 mg, 9.7 mmol) were added. The reaction was stirred at 23° C. for 16 h. The volume of the reaction was reduced by half and water (25 mL) was added. The suspension was extracted with 2:1 ethyl acetate: tetrahydrofuran (3×, 10 mL). The organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was chromatographed on a 4 g Analogix column eluting with 0-10% methanol in dichloromethane. The solid was then dried in a vacuum oven at 50° C. for 18 h to give 253 mg (39% yield) of ethyl 1-((1-(2-(tert-butyldimethylsilyloxy)ethyl)pyrrolidin-3-yl)methyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate as an off white solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([C:42]([CH3:44])=[CH2:43])[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[O:54]=O>C(O)C.[Fe+2]>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([C:42]([OH:54])([CH3:44])[CH3:43])[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=O
Reactant: C=C(C)c1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Agent: [Fe+2]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C(C)(C)O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Reaction time: 1 h

Procedure:
Methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,22,28-trimethyl-5-(prop-1-en-2-yl)-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (50 mg, 0.072 mmol, 1 equiv) was dissolved in ethanol (0.86 mL). To this solution was added iron(II) phthalacyanine (4.07 mg, 7.16 μmol, 0.1 equiv) and sodium borohydride (5.42 mg, 0.143 mmol, 2 equiv). The reaction was stirred under air for 1 hour. No reaction. The mixture was then placed under oxygen balloon and stirred for 2 hours. To this solution was added 10 mg catalyst and 10 mg sodium borohydride and stirred under the oxygen balloon again. It was found that the vial emitted heat and the solution of the reaction turned to dark purple and back to blue again. The reaction was stirred overnight. The reaction completed 30% by LCMS. It was used as is for the next reaction. LCMS (ESI, M+1): 716.4.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:25])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.C[O:27][C:28]([C@H:30]1[CH2:34][C@H:33]([N:35]2[CH:39]=[C:38](I)[CH:37]=[N:36]2)[CH2:32][N:31]1C(OCC1C=CC=CC=1)=O)=[O:29].[F-].O1CCOCC1>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.O>[NH2:25][C:11]1[N:12]=[CH:13][C:14]([C:38]2[CH:37]=[N:36][N:35]([C@@H:33]3[CH2:32][NH:31][C@@H:30]([C:28]([OH:29])=[O:27])[CH2:34]3)[CH:39]=2)=[CH:15][C:10]=1[C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: COC(=O)[C@H]1C[C@H](n2cc(I)cn2)CN1C(=O)OCc1ccccc1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4s3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2cnn([C@@H]3CN[C@@H](C(=O)O)C3)c2)cc1-c1nc2ccccc2s1
Temperature: 60 °C

Procedure:
A mixture of 3-benzothiazol-2-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (BB8) (151 mg, 0.428 mmol), (2R,4S)-4-(4-iodopyrazol-1-yl)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (177 mg, 0.389 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol), potass fluoride (67.8 mg, 1.17 mmol), and 4:1 dioxane:water (4 mL) was heated in the microwave reactor at 85° C. for 30 min. The solution was dry-loaded onto silica gel for column chromatography, eluting with 2→5% MeOH/DCM. The fractions containing the product were concentrated in vacuo and dissolved in conc. HCl. The material was heated to 60° C. for 3 h in a sealed tube. The solvent was removed on the corrosive pump to afford the title compound as an orange solid. 1H NMR (400 MHz, CD3OD): δ=2.55-2.67 (m, 1H), 2.74 (br. s., 1H), 3.76-3.87 (m, 2H), 4.45 (t, J=8.6 Hz, 1H), 5.25 (dd, J=6.1, 3.0 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H), 7.49-7.55 (m, 1H), 7.88 (s, 1H), 7.97 (d, J=7.6 Hz, 1H), 8.02 (d, J=7.8 Hz, 1H), 8.06 (s, 1H), 8.16 (d, J=2.0 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([CH3:23])[N:16]=1)=[O:13])(=[O:10])=[O:9].[CH2:24]=[C:25]=[O:26]>ClCCl>[C:25]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([CH3:23])[N:16]=1)=[O:13])(=[O:10])=[O:9])(=[O:26])[CH3:24]
Reactant: C=C=O
Reactant: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2N)n1
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2NC(C)=O)n1
Reaction time: 0.25 h

Procedure:
2-Amino-N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]benzenesulfonamide (1.0 g) suspended in 25 ml of dichloromethane was treated with ketene for 10 minutes (ca. 0.4 mole/hr). The mixture was allowed to stand and after 15 minutes a light orange solution resulted. Evaporation of the solvent gave an orange glassy oil which was triturated with water and allowed to stand for 16 hours. The white solid thus obtained was removed by filtration and dried in-vacuo to yield 0.24 g of the desired product, m.p. 161°-162°. The product showed absorption peaks by proton NMR at 4.0 (singlet, 3H); 2.5 (singlet, 3H) and 2.1 (singlet, 3H) consistent for the acetylated derivative. The infrared absorption spectrum showed peaks at 1700, 1695, 1610 and 1580 also confirming the desired acylation.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[N:5][CH:4]=1)[CH3:2].C([N-]C(C)C)(C)C.[Li+].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25](=[O:32])[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1>O1CCCC1>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25]([OH:32])([CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[N:5][CH:4]=1)[CH3:2])[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: CCc1ccnnc1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(c1ccnnc1)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
Treatment of 4-ethylpyridazine (2.16 g) with lithium diisopropylamide (0.02 mole) in dry tetrahydrofuran followed by 1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (5.12 g) according to the method of Example 9(ii) gave the title compound, diastereoisomeric pair A, (1.24 g), m.p. 174°-177°;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].C1CCNCC1.[F:23][C:24]1[C:29]([C:30](Cl)=[O:31])=[C:28]([F:33])[C:27]([F:34])=[C:26]([F:35])[C:25]=1[F:36]>O1CCCC1>[F:23][C:24]1[C:25]([F:36])=[C:26]([F:35])[C:27]([F:34])=[C:28]([F:33])[C:29]=1[C:30]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:31]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)c(F)c(F)c(F)c3F)c2)CC1
Reaction time: 0.17 h
Yield: 107.5 %

Procedure:
A mixture of 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and (piperidinomethyl)-polystyrene (100 mg, 0.260 mmol) in tetrahydrofuran (2 mL) was allowed to stand for 10 min. Pentafluorobenzoyl chloride (33 μL, 0.229 mmol) was added to the reaction mixture. The reaction mixture was mixed for 2 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. Glacial acetic acid (0.5 mL) was added to the filtrate solution and the solution was mixed. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed with methanol to remove impurities, then treated with a 7M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 51 mg (>100%) of the title compound.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:7][N:6]1[C:2]([C:22]2[CH:21]=[CH:20][C:19]([O:18][C:17]([F:16])([F:28])[F:29])=[CH:24][CH:23]=2)=[C:3]([C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[N:4]=[CH:5]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-(trifluoromethoxy)phenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C17H11F3N4O, 345. Found, 345.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH2:17]([O:19][C:20]([C:22]1[NH:23][N:24]=[C:25]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=1)=[O:21])[CH3:18].[Br:35][CH2:36][CH2:37]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:17]([O:19][C:20]([C:22]1[N:23]([CH2:37][CH2:36][Br:35])[N:24]=[C:25]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=1)=[O:21])[CH3:18]
Reactant: OCCBr
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(COc2ccccc2)nn1CCBr
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
Di-tert-butyl azodicarboxylate (1.68 g, 7.30 mmol) was added portionwise to a stirred solution of 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.0 g, 4.06 mmol), 2-bromoethanol (0.58 mL, 8.12 mmol) and triphenylphosphine (1.92 g, 7.30 mmol) in THF (24.5 mL) at 0° C. The mixture was stirred at 120° C. for 30 minutes under microwave irradiation and then the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; DCM). The desired fractions were collected and concentrated in vacuo to yield 2-(2-bromoethyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.08 g, 71% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:25])[O:5][C:6]1[C:7]([CH3:24])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:23])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:36]=[C:37]=[O:38])=[O:35])=[CH:29][CH:28]=1>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:25])[O:5][C:6]1[C:7]([CH3:24])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:37]([NH:36][C:34](=[O:35])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)=[O:38])=[CH:18][C:17]=1[F:23])[CH3:2]
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CCNC(=O)Oc1cn2ncnc(Oc3ccc(N)cc3F)c2c1C
Solvent: ClCCl
Product: CCNC(=O)Oc1cn2ncnc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)c2c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl ethylcarbamate (10 mg, 0.029 mmol) in CH2Cl2 (1 mL) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate (2 mL, 0.25 M in dichloroethane). The reaction was stirred at room temperature for 1 h, LC/MS analysis indicated consumption of starting carbamate. The mixture was concentrated in vacuo and the residue was suspended in methanol and filtered to give the title compound. The filtrate was purified by flash chromatography to provide more of the title compound as a pale yellow solid (combined yield 5.9 mg, 40%). 1H NMR (CDCl3) δ 10.63 (s, 1H), 8.42 (s, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.67 (dd, 1H, J=12.1, 2.2 Hz), 7.28 (m, 4H), 7.10 (m, 2H), 3.73 (s, 3H), 3.36 (m, 2H), 2.48 (s, 3H), 1.26 (m, 3H); MS(ESI+) m/z 525 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=1.[OH-].[Li+]>C(O)C.O.O>[F:1][C:2]([F:17])([F:18])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCc1cccc(OC(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCc1cccc(OC(F)(F)F)c1
Temperature: 15 °C
Reaction time: 2 h

Procedure:
To a mixture of 158d (11.0 g, 42 mmol) in ethanol/water (150 mL/100 mL) was added lithium hydroxide (8.8 g, 210 mmol). See FIG. 4. The resulting mixture was stirred at 15° C. for 2 h. The mixture was diluted with water and extracted with EtOAc (200 mL×3). The organic layers were dried over anhydrous sodium sulfate and concentrated to afford 3-(3-(trifluoromethoxy)phenyl)propanoic acid 158e as a colorless oil.
Reaction SMILES: [CH:1](=[CH:8]/[C:9](=[O:11])[CH3:10])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.O.O1CCO[CH2:19][CH2:18]1>CCCCCC>[C:2]1([CH:1]([CH2:18][CH3:19])[CH2:8][C:9](=[O:11])[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)/C=C/c1ccccc1
Reactant: C1COCCO1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: O
Product: CCC(CC(C)=O)c1ccccc1
Temperature: 22 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
143 mg of CuBr is added to 1.46 g (10 mmol) of cis/trans-benzylideneacetone (3-phenyl-but-3-en-2-one) in 20 ml of absolute dioxane. 11 ml (11 mmol) of a 1 molar solution of trimethyl aluminum in hexane is added to the reaction at room temperature under nitrogen atmosphere and, after completion of the addition, stirred for 10 minutes at 22° C. For hydrolysis of the reaction solution, 1 ml of water dissolved in 5 ml of dioxane is carefully added to the reaction. It is stirred for 10 minutes more and the inorganic precipitate filtered off with dioxane is washed again. The dioxane solution is concentrated by evaporation on a rotary evaporator and the residue is chromatographed on silica gel with ethyl acetate/hexane as eluent. After concentration by evaporation of the fractions, 1.37 g of 4-phenyl-hexan-2-one (78% of theory) is obtained a colorless liquid.
Reaction SMILES: [OH:1][C@H:2]([CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](O)=[CH:13][C:12]=1[CH3:18]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][C@@H:2]([CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][C:12]=1[CH3:18]
Reactant: COC(=O)[C@H](O)C(C)C
Reactant: Cc1cc(O)ccc1Cl
Product: COC(=O)[C@@H](Oc1ccc(Cl)c(C)c1)C(C)C

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the (R)-methyl 2-hydroxy-3-methylbutanoate instead of the (S)-methyl 2-hydroxypropanoate and the 4-chloro-3-methylphenol instead of the m-cresol.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:14][CH2:13]3)=[O:11])[S:8][C:4]=2[CH:3]=1.F[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:13][CH2:14]3)=[O:11])[S:8][C:4]=2[CH:3]=1)([O-:26])=[O:25]
Reactant: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccc(Oc3cccc([N+](=O)[O-])c3)cc2s1)C1CC1
Temperature: 150 °C
Reaction time: 15 h
Yield: 33.9 %

Procedure:
A mixture of N-(6-hydroxy-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (3.54 g, 15.1 mmol), 1-fluoro-3-nitrobenzene (2.24 g, 15.9 mmol), potassium carbonate (6.26 g, 45.3 mmol) and N,N-dimethylformamide (30 mL) was stirred at 150° C. for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (1.82 g, 37%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9](=O)[CH2:10][S:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[NH:8][C:9](=[S:14])[CH2:10][S:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CSc2cccc(Cl)c2N1
Agent: Cl
Solvent: c1ccncc1
Product: S=C1CSc2cccc(Cl)c2N1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 195.8 %

Procedure:
5-Chloro-2,3-dihydro-1,4-benzothiazine-3-one (2.0 g) and phosphorus pentasulfide (2.0 g) were added to pyridine (5 ml), followed by stirring at 120° C. for 20 minutes. The reaction mixture was then poured into a dilute hydrochloric acid (50 ml), and the precipitated crystals were filtered, washed with water, dried and recrystallized from ethanol to obtain 1.9 g of the objective 5-chloro-2,3-dihydro-1,4-benzothiazine-3-thione (m.p. 138°-140° C.).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].COCCOC.[NH2:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1>CCO>[CH2:7]([O:6][C:4]([C:3]1[N:16]=[C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]2[CH:2]=1)=[O:5])[CH3:8]
Reactant: Nc1cnccn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)c1cn2ccncc2n1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Ethyl bromopyruvate (62.9 g) was added to the DME (258 mL) solution of 2-aminopyrazine (24.8 g) at room temperature and stirred for 2.5 h. The reaction mixture was cooled to 0° C. and stirred for 30 min to afford a pale brown precipitate. The precipitate was filtered and washed with Et2O to give pale brown crystals. The suspension of the precipitate (66.1 g) in EtOH (1.29 L) was heated at reflux temperature to turn to clear solution. After refluxing for 2 h, the reaction mixture was concentrated under reduced pressure, then mixed with CHCl3 and saturated NaHCO3aq. The mixture was filtered through a pad of Celite and the separated organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with CHCl3-MeOH (99/1˜97/3), and collected fractions were concentrated under reduced pressure followed by recrystallization from CHCl3-Et2O. The titled compound was obtained as pale pink crystals. Yield: 10.9 g, 22%).