Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH2:21].CS([C:25]1[N:30]=[CH:29][C:28]2=[CH:31][CH:32]=[C:33]([N:34]3[CH:38]=[CH:37][CH:36]=[N:35]3)[N:27]2[N:26]=1)=O.C(N(CC)C(C)C)(C)C.COCC(O)C>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:21][C:25]1[N:30]=[CH:29][C:28]2=[CH:31][CH:32]=[C:33]([N:34]3[CH:38]=[CH:37][CH:36]=[N:35]3)[N:27]2[N:26]=1
Reactant: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1N
Reactant: CS(=O)c1ncc2ccc(-n3cccn3)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: COCC(C)O
Product: COc1cc(N2CCC(N3CCOCC3)CC2)ccc1Nc1ncc2ccc(-n3cccn3)n2n1

Procedure:
To a RB flask under argon were introduced 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (300 mg, 1 mmol), 1H-Pyrazole (88.5 mg, 1.30 mmol), Cesium carbonate (801 mg, 2.46 mmol), Copper(I) iodide (50 mg, 0.3 mmol) and DMF (5 mL). The mixture was degassed for few minutes and heated at 110° C. overnight under argon. Solvent was removed and the mixture was taken in EtOAc and was passed through a pad of celite. Solvent evaporation gave the crude product which was purified by flash chromatography (ISCO, hexane :EtOAc 3:1). 2-Methylsulfanyl-7-pyrazol-1-yl-pyrrolo[2,1-f][1,2,4]triazine was isolated as a yellow syrup (23, 8%). LCMS (E/I+) 232 (M+H). 2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenylamine (47.1 mg, 0.162 mmol), 2-Methanesulfinyl-7-pyrazol-1-yl-pyrrolo[2,1-f][1,2,4]triazine (20 mg, 0.08 mmol), N,N-Diisopropylethylamine (30 uL, 0.2 mmol) and 1-Methoxy-2-propanol (200 uL,) were combined in a microwave vial. The reaction was microwaved at 200° C. for 2.5 hours, taken up in DMSO, purified by Gilson RP-HPLC. The product, [2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-(7-pyrazol-1-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine was isolated as a tan solid (8 mg, 21%). LCMS (E/I+) 475 (M+H). NMR 1H (DMSO-d6)-9.75 (br s, 1H), 8.94 (s, 1H), 8.58 (d, 1H, J=2.09 Hz), 7.94 (s, 1H), 7.83 (s, 1H), 7.67 (d, 1H, J=8.72 Hz), 6.94 (s, 2H), 6.70 (s, 1H), 6.60 (s, 1H), 6.52 (d, 1H, J=8.74 Hz), 4.04-3.13 (series of m, s along with the water peak, 14H), 2.71 (m, 2H), 2.15 (d, 2H, J=11.30 Hz), 1.72 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: NCc1ccccn1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(NCc3ccccn3)nc21
Temperature: 130 °C
Reaction time: 0.03 h
Yield: 38.8 %

Procedure:
A mixture of 0.165 g (0.47 nmmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one, 1.08 g (10.0 mmol) of 2-(aminomethyl)pyridine and 0.5 mL of dimethylformamide was heated with stirring in a 130° C. oil bath. After 2 minutes, solution was complete. After 2 hours, the excess amine and dimethylformamide were evaporated at reduced pressure. Ether (5 mL) was added to the residue. Crystals immediately developed. Water (5 mL) was added, and the entire mixture was filtered. The cake was washed 5 mL of ether, 5 mL of water, and then dried; wt 0.164 g. Recrystallization from ethyl acetate gave 0.075 g of pure product; mp 198-201° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:16]1[CH:17]=[CH:18][N:19]=[C:20]2[C:25]=1[N:24]=[CH:23][C:22]([O:26][CH3:27])=[CH:21]2.O>CN(C=O)C>[CH3:27][O:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[CH:17][CH:18]=[N:19]2)=[N:24][CH:23]=1
Reactant: COc1cnc2c(Cl)ccnc2c1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc2c(Oc3ccc(N)cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Five 20 mL microwave vials were each charged with 4-aminophenol (0.700 mg, 33 mmol) and 3 equivalents of cesium carbonate in 6.0 ml of DMF. The mixture was stirred at RT for 10 minutes. Following addition of 8-chloro-3-methoxy-1,5-naphthyridine (1 g, 26 mmol), the reaction vessels were capped and irradiated at 150° C. for 15 min in the microwave, at which time the reaction was determined complete by LCMS. The mixture was allowed to cool to ambient temperature and material from the five vessels was combined. A deep brown solid crashed out with addition of water. Filtered solids, washed with water and dried overnight in the vacuum oven to afford 4-(7-methoxy-1,5-naphthyridin-4-yloxy)benzenamine as a brown solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C@@:11]([C@@H:14]3[C@@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]3([CH3:22])[CH3:21])([OH:13])[CH3:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[N:30]([Si](C)(C)C)=[C:31]=[O:32]>ClCCl>[OH:13][C@@:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH2:1][N:2]([C:31]([NH2:30])=[O:32])[CH2:3][CH2:4]2)([C@@H:14]1[C@@H:19]([CH3:20])[CH2:18][CH2:17][CH2:16][C:15]1([CH3:21])[CH3:22])[CH3:12]
Reactant: C[Si](C)(C)N=C=O
Reactant: C[C@H]1CCCC(C)(C)[C@@H]1[C@@](C)(O)c1ccc2c(c1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CCCC(C)(C)[C@@H]1[C@@](C)(O)c1ccc2c(c1)CCN(C(N)=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a solution of compound of the crude product of Example 13c (28 mg, 0.1 mmol) in dichloromethane (2 mL) was added triethylamine (55 mg, 0.5 mmol) and isocyanatotrimethylsilane (47 mg, 0.4 mmol). The reaction was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with water, saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound as a yellow oil (15 mg). Mass spectrum (LC ESI +ve) m/z 345 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][NH:17][C:18]([CH3:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH:21]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@@H:22]([C:29](O)=[O:30])[CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26]>>[NH:21]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@@H:22]([C:29]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][NH:17][C:18]([CH3:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4])=[O:30])[CH2:23][CH2:24][S:25]([CH3:28])(=[O:26])=[O:27]
Reactant: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CN
Reactant: CC(C)(C)OC(=O)N[C@H](CCS(C)(=O)=O)C(=O)O
Product: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCS(C)(=O)=O)NC(=O)OC(C)(C)C
Yield: 52.7 %

Procedure:
Using H-Gly-Phe-NHNH-COCH3 (0.69 g) and BOC-(D)-Met(O2)-OH (0.66 g), the desired compound (0.67 g) is obtained in a similar manner to (III)of Example 45. m.p. 198°-199° C.(decomp.), [α]D23 -2.5°(c=0.49, DMF), Rf1 =0.25.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:23]2[CH:24]=[CH:25][C:20]([N:19]([CH3:29])[CH3:18])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Product: CN(C)c1ccc(-c2ccc(S(=O)(=O)NCCCCCO)cc2)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 4-dimethylaminophenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 22.7, 28.9, 32.0, 39.9, 42.6, 60.5, 112.6, 125.5, 125.8, 127.1, 127.8, 137.5, 143.9 and 150.5.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[CH3:11][N:12]([CH3:26])[C:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.FC(F)(F)S(O)(=O)=O.[OH-:35].[Na+]>ClCCl>[CH3:11][N:12]([CH3:26])[C:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][C:16]([C:1]2[O:35][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[CH3:3])([C:3]2[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[CH3:1])[CH2:15][CH2:14]1
Reactant: Cc1coc2ccccc12
Reactant: [OH-]
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(C2(c3oc4ccccc4c3C)CCC(c3ccccc3)(N(C)C)CC2)oc2ccccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3-methylbenzofuran (354 mg, 3 mmol) together with 4-(dimethylamino)-4-phenylcyclohexanone (651 mg, 3 mmol, synthesis cf. WO2008009415, ketone unit Ket-10) was dissolved in dichloromethane (25 ml) and mixed with trifluoromethane sulphonic acid (0.3 ml, 3.4 mmol). The batch was stirred for 20 h at RT. For work up the reaction mixture was mixed with 2N NaOH (10 ml). The mixture was stirred a further 20 min. After separation of the phases the aqueous phase was extracted with dichloromethane (3×20 ml). The combined organic extracts were dried over MgSO4 and then concentrated to low volume. The raw product (950 mg) obtained was purified by column chromatography (mobile solvent: EtOAc) and then recrystallised from ethanol (60 ml).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[CH:8]1([NH:12][C:13]2[N:14]=[C:15]3[CH2:38][CH2:37][NH:36][CH2:35][C:16]3=[N:17][C:18]=2[N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[F:34])[CH2:21][CH2:20]2)[CH2:11][CH2:10][CH2:9]1.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42].C(N(CC)CC)C>C(Cl)Cl>[CH:8]1([NH:12][C:13]2[N:14]=[C:15]3[CH2:38][CH2:37][N:36]([C:41]([N:40]([CH3:44])[CH3:39])=[O:42])[CH2:35][C:16]3=[N:17][C:18]=2[N:19]2[CH2:20][CH2:21][CH:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[F:34])[CH2:23][CH2:24]2)[CH2:11][CH2:10][CH2:9]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CCNC4)CC2)c(F)c1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CCN(C(=O)N(C)C)C4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-cyclobutyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (10.6 mg, 0.020 mmol), dimethylcarbamic chloride (4.2 mg, 0.039 mmol) and triethylamine (5.9 mg, 0.059 mmol) in DCM (200 μL) was stirred at room temperature for 30 min. The mixture was purified by HPLC Method A to give the title compound as a TFA salt (7.1 mg, 59.2%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.77-1.87 (m, 2H), 1.90-2.00 (m, 2H), 2.03-2.15 (m, 4H), 2.39-2.49 (m, 2H), 2.81-2.87 (m, 2H), 2.90 (s, 6H), 2.98-3.08 (m, 2H), 3.38-3.47 (m, 2H), 3.54 (t, J=5.8 Hz, 2H), 3.76 (s, 3H), 4.26 (s, 2H), 4.33-4.47 (m, 2H), 6.67 (dd, J=9.1, 1.5 Hz, 1H), 6.74 (dd, J=12.8, 2.9 Hz, 1H), 7.08 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+ 499.4.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[CH2:34](OC(OCC)OCC)C>ClCCCl.C1CCN2C(=NCCC2)CC1>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:26][CH:25]=[C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:23]=3)[N:1]=[CH:34]2)[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1cc(NC(=O)c2cc(Oc3ccccc3)ccc2N)ccc1OCCN1CCCC1
Reactant: CCOC(OCC)OCC
Solvent: ClCCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(-n2cnc3ccc(Oc4ccccc4)cc3c2=O)ccc1OCCN1CCCC1
Temperature: 80 °C

Procedure:
A solution of 2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-phenoxy-benzamide [Example D1] (25 mg, 0.055 mmol) in 1,2-dichloroethane (1 ml) was treated with triethylorthoformate (2 ml) and the mixture heated to 80° C. for 16 hours. The mixture was cooled, 1 drop of DBU added and the mixture evaporated. The residue was subjected to flash chromatography on silica gel eluting with (methanol-dichloromethane-aqueous ammonia) to give the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.[CH3:21][S:22](C1C=CC(CNC)=CC=1)(=[O:24])=[O:23].CS(Cl)(=O)=O>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:16][CH:15]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1
Reactant: CNCc1ccc(S(C)(=O)=O)cc1
Agent: CS(=O)(=O)Cl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NS(C)(=O)=O)cc2)C1
Product: Cl

Procedure:
The process is analogous to the method described in example 82, starting from the compound of example 17, intermediate 1, and methanesulfonyl chloride.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:64])[C:49]4[C:50]([O:56][C:57]=3[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[C:51]([Cl:55])[N:52]=[CH:53][CH:54]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[ClH:55].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:64])[C:49]4[C:50]([O:56][C:57]=3[C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)=[C:51]([Cl:55])[N:52]=[CH:53][CH:54]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Cl)nccc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: Cl
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Cl)nccc4c3=O)cc2)CCC1

Procedure:
Following the procedure of 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(8-chloro-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as the free base. The residue was dissolved in a mixture of MeOH (2 mL), water (3 mL) and 1 M HCl (0.1 mL) and then chromatographed on a 5 g C18 cartridge {gradient 40 to 70% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound (12.5 mg, 75%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.45 (d, J=5.1 Hz, 1H), 8.02 (d, J=5.1 Hz, 1H), 7.53-7.48 (m, 4H), 7.46-7.41 (m, 1H), 7.39-7.32 (m, 4H), 2.82-2.75 (m, 2H), 2.63-2.55 (m, 2H), 2.30-2.19 (m, 1H), 2.03-1.92 (m, 1H). LCMS (Method E): RT=3.54 min, [M−NH2]−=386/388.
Reaction SMILES: [F:1][C:2]([F:8])(F)S(O)(=O)=O.S1CCCSC1=[C:15]1[CH2:24][CH2:23][C:18]2([O:22][CH2:21][CH2:20][O:19]2)[CH2:17][CH2:16]1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.[OH-].[Na+]>ClCCl.CCN(CC)CC>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]([F:8])([F:1])[CH:15]2[CH2:16][CH2:17][C:18]3([O:19][CH2:20][CH2:21][O:22]3)[CH2:23][CH2:24]2)=[CH:28][CH:27]=1
Reactant: C1CSC(=C2CCC3(CC2)OCCO3)SC1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(Oc1ccc(Br)cc1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoromethanesulfonic acid (0.681 mL, 7.82 mmoles) was added dropwise to a stirred solution of 8-[1,3]dithian-2-ylidene-1,4-dioxa-spiro[4,5]decane (2000 mg, 7.740 mmoles) in 25 mL of dichloromethane at −22° C. The solution was allowed to warm to room temperature and stirred for 30 minutes The black reaction mixture was cooled to −72° C. and a solution of 4-bromo-phenol (2010 mg, 11.6 mmoles) and triethylamine (1.90 mL, 13.6 mmoles) in 25 mL of dichloromethane was added (solution turned red). The reaction was allowed to stir for an hour at −72° C., before NEt3.3HF (6.31 mL, 38.7 mmoles) was added. After 5 minutes a suspension of DBH (1,3-dibromo-5,5-dimethylhydanthoin) (11.1 g, 38.7 mmoles) in 25 mL's of dichloromethane was added in portions over 30 minutes (solution turned greenish/black). The solution was stirred for an additional hour, then warmed to 00° C. and poured into a solution of 1 N NaOH. The organic layer was separated, washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via silica gel chromatography and was eluted with 20% ethyl acetate 80% heptane to 100% ethyl acetate for 45 minutes. The isolated product was taken on directly to the next step. (2.811 g, 24.9%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([NH2:14])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)[CH3:2].C(O)(=O)C.CO[CH:25]1[CH2:29][CH2:28][CH:27](OC)O1>CCCCCCC>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([N:14]2[CH:25]=[CH:29][CH:28]=[CH:27]2)=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(OCC)c(N)c(OCC)c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: CCCCCCC
Product: CCOC(=O)c1cc(OCC)c(-n2cccc2)c(OCC)c1
Yield: 82 %

Procedure:
To a solution of 4-amino-3,5-diethoxy-benzoic acid ethyl ester (3.0 g, 11.84 mmol, 1.0 equiv; prepared as described in I. Kompis and A. Wick, Helv. Chim. Acta 1977, 60, 3025-3034) in heptane (10 mL) and conc. acetic acid (0.2 mL) was added 2,5-dimethoxy-tetrahydro-furan (1.88 g, 14.21 mmol, 1.2 equiv). After heating to reflux for 5 h, a Dean-Stark apparatus was attached and the reaction mixture heated for an additional time period of 5 h. Filtration of the crude reaction mixture and crystallization at 0° C. from heptane provided 2.94 g (82%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.15 (t, J=7.0 Hz, 6H), 1.27 (t, J=7.1 Hz, 3H), 3.98 (q, J=7.0 Hz, 4H), 4.28 (q, J=7.1 Hz, 2H), 6.07-6.08 (m, 2H), 6.73-6.74 (m, 2H), 7.22 (s, 2H). 13C NMR (75 MHz, DMSO): δ 14.11, 14.35, 61.06, 64.57, 106.87, 107.64, 122.61, 123.33, 129.29, 153.75, 165.06. MS (ISP): 303.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]2[C:9]([C:10]=1[C:11](=[O:15])[C:12]([NH2:14])=[O:13])=[CH:8][C:7]([N+:16]([O-:18])=[O:17])=[CH:6][CH:5]=2.[BH4-].[Na+]>CCO>[CH3:1][C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]2[C:9]([C:10]=1[CH:11]([OH:15])[C:12]([NH2:14])=[O:13])=[CH:8][C:7]([N+:16]([O-:18])=[O:17])=[CH:6][CH:5]=2
Reactant: Cc1c(C(=O)C(N)=O)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(C(O)C(N)=O)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a mixture of 1.04 g (3.1 mmol) of 2-methyl-5-nitro-1-(phenylmethyl)-1H-indole-3-glyoxylic acid amide in 30 mL of EtOH was added 148 mg (3.9 mmol) of NaBH4, the mixture stirred for 1.0 hour and concentrated at reduced pressure. The residue was stirred with water and EtOAc and the insoluble material filtered to give 1.05 mg (100% yield of 2-methyl-5-nitro-1-(phenylmethyl)-1H-indole-3-glycolic acid amide, mp, 120-124° C.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>C(O)C>[C:4]1([CH2:3][CH2:2][C:1]([O:11][CH2:12][CH3:13])=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C=Cc1ccccc1
Reactant: [H][H]
Solvent: CCO
Product: CCOC(=O)CCc1ccccc1

Procedure:
A solution of 30 g ethyl cinnamate in 100 ml ethanol containing 2.0 g catalyst, as prepared in Example 3, in a 250 ml stainless steel autoclave may be hydrogenated at 1200 psig hydrogen and 170° C. for about 1.5 hr. to afford ethyl 3-phenylpropionate.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[N:7]([O])[C:6]([CH3:10])([CH3:9])[CH2:5][CH2:4][CH2:3]1.[C:12]([O:16]N=O)(C)([CH3:14])[CH3:13].N[C:20]1[CH:25]=CC=C[CH:21]=1>N1C=CC=CC=1>[O:16]([N:7]1[C:2]([CH3:11])([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1([CH3:10])[CH3:9])[C:12]1[CH:14]=[CH:25][CH:20]=[CH:21][CH:13]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)ON=O
Reactant: CC1(C)CCCC(C)(C)N1[O]
Solvent: c1ccncc1
Product: CC1(C)CCCC(C)(C)N1Oc1ccccc1
Yield: 68.6 %

Procedure:
The procedure of Example 5 is repeated using 1.95 g (12.5 mmol) of 2,2,6,6-tetramethylpiperidine-1-oxyl, 3.09 g (30.0 mmol) of tert-butylnitrite and 228 mg (˜0.125 mmol) of phosphomolydbic acid hydrate (H3PMo12O40) in 100 mL of pyridine and 2.32 g (25 mmol) of aniline in 5 mL of pyridine. The crude is purified by vacuum flash chromatography (heptane) to give 2.0 g of a colorless oil in 68.7% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C(=O)C>[CH2:30]([N:11]([CH2:12][C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[CH:16][CH:17]=1)[S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:9])=[O:10])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3cccc(Cl)c3)s2)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(Cc3ccccc3)S(=O)(=O)c3cccc(Cl)c3)s2)c1

Procedure:
In analogy to example 1, step 2, 3-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide was reacted with sodium hydride in N,N-dimethylacetamide at 0° C. followed by reaction with benzyl bromide at r.t. overnight to give N-benzyl-3-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as an off-white solid. MS: 549.3 ([M+NH4]+)
Reaction SMILES: [NH2:1][C:2]1[C:17]([F:18])=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:19])[CH:3]=1.C(N(C(C)C)CC)(C)C.COC1C=CC(CNC2N=CN=C(OC3C=CC(N[C:51]([NH:53][C:54](=[O:63])[CH2:55][C:56]4[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=4)=[O:52])=CC=3F)C=2)=CC=1.FC1C=CC(CC(N=C=O)=O)=CC=1>C1COCC1>[C:13]([C:9]1[CH:8]=[C:7]([O:6][C:5]2[C:4]([F:19])=[CH:3][C:2]([NH:1][C:51]([NH:53][C:54](=[O:63])[CH2:55][C:56]3[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=3)=[O:52])=[C:17]([F:18])[CH:16]=2)[CH:12]=[CH:11][N:10]=1)(=[O:14])[NH2:15]
Reactant: NC(=O)c1cc(Oc2cc(F)c(N)cc2F)ccn1
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Agent: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)c1cc(Oc2cc(F)c(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Reaction time: 3.5 h
Yield: 90.8 %

Procedure:
To a homogeneous mixture of 4-(4-amino-2,5-difluorophenoxy)picolinamide (0.15 g, 0.57 mmol) in THF (5 mL) was added diisopropylethylamine (0.10 mL, 0.57 mmol). The mixture was stirred for two minutes at ambient temperature before 2-(4-fluorophenyl)acetyl isocyanate (Compound D of Example 11, 0.36 M in toluene, 2.0 mL, 0.72 mmol) was added. After 3.5 hours, 2-(4-fluorophenyl)acetyl isocyanate (0.36 M in toluene, 2.0 mL, 0.72 mmol) was added to the reaction mixture. After an additional two hours, 2-(4-fluorophenyl)acetyl isocyanate (0.36 M in toluene, 2.0 mL, 0.72 mmol) was added to the reaction mixture. The mixture was then stirred for 16 hours before being concentrated in vacuo. The residue was treated with Et2O and sonication and the resultant white solid was removed by filtration. The solid was treated with Et2O and sonication two more times before vacuum filtration afforded a white solid (0.23 g, 91%). 1H NMR (DMSO-d6) δ 11.29 (s, 1H), 10.92 (s, 1H), 8.56 (d, 1H, J=5.6 Hz), 8.21-8.26 (m, 1H), 8.16 (br s, 1H), 7.76 (br s, 1H), 7.66-7.71 (m, 1H), 7.12-7.44 (m, 6H), 3.77 (s, 2H); MS (ESI+) m/z 445 (M+H)+.