Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([S:22]([N:25](CC3C=CC(OC)=CC=3OC)[C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[C:17]([F:43])[CH:16]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[C:7]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([S:22]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)(=[O:23])=[O:24])=[C:17]([F:43])[CH:16]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3cccnc3N)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 82.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-2-(2-aminopyridin-3-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (0.06 g, 0.09 mmol) prepared in Example 69c, triethylsilane (0.07 mL), trifluoroacetic acid (0.09 mL) and dichloromethane (0.90 mL), to yield the title compound (34.2 mg, 82%) as a colorless solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH2:33][CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:32])[NH:33][CH:34]5[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC(=O)c2ccc(-c3ccc(-c4nc(-c5ccc(Cl)c(Cl)c5)cs4)cc3C(=O)O)cc2)CC1
Yield: 113.5 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 4-amino-1-methylpiperidine (available from Aldrich Chemical Company, Inc.; 71 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(1-methyl-piperidin-4-ylcarbamoyl)-biphenyl-2-carboxylic acid (135 mg, 116%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.20 (br s, 1H), 8.55 (d, J=7.5 Hz, 1H), 8.49 (s, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.26 (dd, J=8.2, 1.9 Hz, 1H), 8.10 (dd, J=8.3, 2.0 Hz, 1H), 7.92 (d, J=8.3 Hz, 2H), 7.78 (d, J=8.3 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 4.01-4.10 (m, 1H), 3.45-3.51 (m, 2H), 3.05-3.18 (m, 2H), 2.78-2.81 (m, 2H), 2.54 (s, 3H), 2.02-2.10 (m, 2H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[C:5]([F:16])=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[C:5]([F:16])=[C:4]([F:17])[CH:3]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=C1NCCn2c1cc1c(F)c(F)cc(Br)c12
Product: O=C1NCCn2c1cc1c(F)c(F)cc(-c3ccc(F)c(F)c3)c12

Procedure:
The title compound, white solid (72 mg, 86%), MS (ISP) m/z=335.3 [(M+H)+], mp 317.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8,9-difluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 4) (75.3 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[S:8][CH2:9][CH2:10][NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[Cl:14][CH2:15][C:16](Cl)=[O:17]>C1COCC1.C(OCC)(=O)C>[Cl:14][CH2:15][C:16]([N:11]1[CH2:10][CH2:9][S:8][C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]1=2)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCS2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CCl)N1CCSc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
To a stirred solution of 6-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (620 mg, 3.16 mmol) in THF (10 mL) was added 2-chloroacetyl chloride (0.277 mL, 3.48 mmol). The resulting mixture was then stirred at 60° C. for 10 minutes. The mixture was then diluted with ethyl acetate and washed with water (3×), 1:1 water:saturated sodium carbonate, and brine. The organic phase was dried, filtered, and concentrated, giving the desired product (860 mg, 100%). 1H NMR (DMSO-d6) δ 8.36 (d, J=2.1 Hz, 1H), 7.96 (dd, J=8.7, 2.1 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 4.63 (s, 2H), 3.99-3.92 (m, 2H), 3.39-3.33 (m, 2H); ESI-MS (m/z, %): 295 (M+Na, 68), 273 (MH+, 100), 197 (43).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]C(Br)(Br)Br>C(Cl)Cl>[Br:36][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)COc1cccc(CCCO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)COc1cccc(CCCBr)c1
Yield: 66 %

Procedure:
To a stirred solution of methyl 3-(3-hydroxypropyl)phenoxyacetate (2.00 g) in methylene chloride (20 ml) were added successively triphenylphosphine (2.81 g) and tetrabromomethane (3.55 g) at room temperature. The mixture was evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:1) to give the title compound (1.69 g) having the following physical data.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([SH:6])=[CH:2]1.[CH2:7]([C:11]1([CH2:14][CH3:15])[CH2:13][NH:12]1)[CH2:8][CH2:9][CH3:10]>>[NH2:12][C:11]([CH2:14][CH3:15])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][S:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: CCCCC1(CC)CN1
Reactant: Sc1ccsc1
Product: CCCCC(N)(CC)CSc1ccsc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.3 %

Procedure:
To a solution of n-butyl lithium in hexane (194 ml 1.6M) under nitrogen at -78° C. was added diethyl ether(120 ml) and then dropwise 3-bromothiophene (28 ml). The reaction was warmed to -30° C. and then cooled to -50° C. and powdered sulfur (10 g) was added. The reaction was stirred 15 hours at room temperature and then a solution of potassium hydroxide (24 g) in 160 ml water was added and the ether layer was discarded. The aqueous layer was treated at -5° C. with 6N hydrochloric acid (125 ml) and extracted with dichloromethane and the extract was dried over magnesium sulfate. Filtration and solvent removal afforded crude 3-thiophenthiol (14.1 g). The crude 3-thiophenthiol (10 g) was combined with 2-butyl-2-ethylaziridine (12.6 g, Synthetic Example 1(f)) at 0° C. and the reaction was stirred 15 hours at room temperature. The crude reaction product was purified by column chromatography on silica using 5% methanol in diethyl ether as eluant to give the desired product as an oil (16.4 g). 1H NMR is consistent with proposed structure.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:4]=2[N:3]=1.[NH2:22][CH2:23][CH2:24][N:25]([CH3:34])[CH2:26][CH2:27][CH2:28][N:29]([CH2:31][CH2:32][NH2:33])[CH3:30]>ClCCl>[NH2:33][CH2:32][CH2:31][N:29]([CH3:30])[CH2:28][CH2:27][CH2:26][N:25]([CH3:34])[CH2:24][CH2:23][NH:22][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:4]=2[N:3]=1
Reactant: COc1ccc2c3c(c(Cl)nc2c1)C(=O)c1cnccc1-3
Reactant: CN(CCN)CCCN(C)CCN
Solvent: ClCCl
Product: COc1ccc2c3c(c(NCCN(C)CCCN(C)CCN)nc2c1)C(=O)c1cnccc1-3
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 6-chloro-3-methoxy-5,9-diaza-benzo[c]fluoren-7-one (50.8 mg) (the compound of Reference Example 1c-2) and N,N′-bis-(2-amino-ethyl)-N,N′-dimethyl-propane-1,3-diamine (0.5 ml) was stirred at 50° C. for 4 hours. The reaction mixture was diluted with dichloromethane. The solution was washed with saturated NaHCO3 solution and dried over magnesium sulfate. The organic layer was evaporated to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol-ammonia water (25%)=90:10:1. The desired product (49 mg) was obtained as a reddish oil.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][CH:16]1[CH2:33][CH:32]2[CH:18]([C:19](=[O:45])[N:20]([CH3:44])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]3[C:29]([C:35]([NH:37][S:38]([CH:41]4[CH2:43][CH2:42]4)(=[O:40])=[O:39])=[O:36])([NH:30][C:31]2=[O:34])[CH2:28]3)[CH2:17]1.[CH:46]([C:49]1[N:50]=[C:51]([C:54]2[CH:63]=[C:62](O)[C:61]3[C:56](=[CH:57][C:58]([O:65][CH3:66])=[CH:59][CH:60]=3)[N:55]=2)[S:52][CH:53]=1)([CH3:48])[CH3:47].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH:46]([C:49]1[N:50]=[C:51]([C:54]2[CH:63]=[C:62]([O:15][CH:16]3[CH2:33][CH:32]4[CH:18]([C:19](=[O:45])[N:20]([CH3:44])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]5[C:29]([C:35]([NH:37][S:38]([CH:41]6[CH2:42][CH2:43]6)(=[O:40])=[O:39])=[O:36])([NH:30][C:31]4=[O:34])[CH2:28]5)[CH2:17]3)[C:61]3[C:56](=[CH:57][C:58]([O:65][CH3:66])=[CH:59][CH:60]=3)[N:55]=2)[S:52][CH:53]=1)([CH3:48])[CH3:47]
Reactant: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: CN1CCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CC2C1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
DIAD (22 uL, 0.11 mmol) was added to a mixture of the metathesis product 103 (23 mg), 2-(4-isopropyl-1,3-thiazol-2-yl)-7-methoxyquinolin-4-ol (24 mg, 0.08 mmol), and PPh3 (30 mg, 0.11 mmol) in 1 mL dry THF, in an ice bath. The mixture was stirred at rt overnight and then evaporated. The residue (1.2 mL of a 1.5-mL MeCN solution) was purified by prep-HPLC (Hypercarb 7 uL 100×21.2 mm, 40% to 99% aqueous MeCN in 10 min) to give 3.18 mg MV062308 as cream solids (13% yield).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@:13]([CH2:16][O:17][C:18]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)([CH2:14][OH:15])[O:12][C@@H:11]([N:41]2[CH:49]=[C:47]([CH3:48])[C:45](=[O:46])[NH:44][C:42]2=[O:43])[C@@H:10]1[OH:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:51]1([CH3:61])[CH:56]=[CH:55][C:54]([S:57](Cl)(=[O:59])=[O:58])=[CH:53][CH:52]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C@H:9]1[C@@:13]([CH2:16][O:17][C:18]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)([CH2:14][O:15][S:57]([C:54]2[CH:55]=[CH:56][C:51]([CH3:61])=[CH:52][CH:53]=2)(=[O:59])=[O:58])[O:12][C@@H:11]([N:41]2[CH:49]=[C:47]([CH3:48])[C:45](=[O:46])[NH:44][C:42]2=[O:43])[C@@H:10]1[O:50][S:57]([C:54]1[CH:55]=[CH:56][C:51]([CH3:61])=[CH:52][CH:53]=1)(=[O:59])=[O:58])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(OC[C@]2(CO)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@H]2OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@]2(COS(=O)(=O)c3ccc(C)cc3)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](OS(=O)(=O)c3ccc(C)cc3)[C@H]2OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.2 %

Procedure:
To a solution of nucleoside 6 (2.79 g, 3.9 mmol) in anhydrous pyridine (50 cm3) was added a catalytic amount of 4-(N,N-dimethylamino)pyridine and p-toluenesulphonyl chloride (6.50 g, 34 mmol). The mixture was stirred in the dark for 24 h at room temperature under nitrogen. The reaction was quenched by addition of a saturated aqueous solution of sodium hydrogen carbonate (100 cm3) and the resulting mixture was extracted with dichloromethane. The combined organic phase was washed with saturated aqueous solutions of sodium hydrogen carbonate (3×75 cm3) and sodium chloride (2×75 cm3). The separated organic phase was dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol/pyridine (0.5% methanol; 0.5% pyridine, v/v) as eluent to afford nucteoside 7 (2.40 g, 62%) as a yellowish foam after evaporation of the solvents. δC ((CD3)2SO) 163.2 (C-4), 158.2, 145.9, 145.1, 144.3, 136.8, 135.0, 134.9, 134.8, 131.8, 131.6, 130.2, 130.0, 129.7, 128.2, 127.9, 127.8, 127.6, 127.5, 127.5, 127.4, 126.8, 113.3 (DMT, C-6, 2×Ts, benzyl), 150.2 (C-2), 110.8 (C-5), 95.0, 86.2 (DMT, C-4′), 82.2, 81.9 (C-1′, C-2′), 81.2 (C-3′), 72.9 (CH2Ph), 79 (C-5″), 64 (C-5′), 55.1 (2×CH3O), 21.2, 21.2 (2×CH3), 12.0 (5-CH3).
Reaction SMILES: [O:1]=[C:2]1[C:6]([CH2:7][S:8][C:9]2[CH2:10][S:11][C@@H:12]3[C@H:32]([NH:33]C(=O)CC4C=CC=CC=4)[C:31](=[O:43])[N:13]3[C:14]=2[C:15]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[CH:5][CH2:4][O:3]1.CN1CCOCC1>ClCCl>[NH2:33][C@@H:32]1[C:31](=[O:43])[N:13]2[C:14]([C:15]([O:17][CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:16])=[C:9]([S:8][CH2:7][C:6]3[C:2](=[O:1])[O:3][CH2:4][CH:5]=3)[CH2:10][S:11][C@H:12]12
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCC3=CCOC3=O)CS[C@H]12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCC3=CCOC3=O)CS[C@H]12
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Diphenylmethyl 3-(2,5-dihydro-2-oxofuran-3-yl-methylthio)-7β-phenylacetamidoceph-3-em-4-carboxylate (0.83g) was dissolved in dichloromethane (11 ml) and treated with N-methylmorpholine (298μl). The atmosphere was purged with argon and the mixture cooled to -30° C. A solution of phosphorus pentachloride in dichloromethane (10.6 ml of 40 mg ml-1 solution) was added and the reaction stirred at approximately -20° C. for 30 min. Methanol (2.7 ml) was added and the reaction allowed to warm to room temperature. Water (3.6 ml) was then added and the mixture stirred vigorously for 45 min. Dichloromethane was removed using a rotary evaporator and the residue partitioned between ethyl acetate and water. The pH of the solution was adjusted to 6.0 with 1.0M aqueous ammonia before separating the organic phase, washing with water and brine, and finally drying over magnesium sulphate. Evaporation of solvent gave a residue which was purified by chromatography on silica gel (Keiselgel, 7:3 ethyl acetate:hexane) to give the title compound (600 mg). υmax (CH2Cl2) 1780 and 1760cmhu -1; δH (CDCl3) 2.04 (2H, bs) 3.44-3.73 (4H, m), 4.70 (2H, s), 4.77 (1H, d, J 5.0Hz), 4.96 (1H, d, J 4.9Hz), 6.96 (1H, s) 7.11 (1H, s), 7.27-7.46 (10H, m). [mass spectrum: +ve ion (Thioglycerol) MH+ 495].
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[CH3:16].CN(C)[CH:19]=[O:20]>CCCCC.C1COCC1>[CH3:16][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([CH:19]=[O:20])[CH:8]=2)[NH:12][N:11]=1
Reactant: CN(C)C=O
Reactant: Cc1n[nH]c2ccc(Br)cc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1n[nH]c2ccc(C=O)cc12
Reaction time: 0.25 h

Procedure:
Tetrahydrofuran (600 ml) was cooled down to −78° C. under argon atmosphere. At this temperature, a 1.7 M solution of tert-butyllithium in n-pentane (200 ml) was added dropwise. After 15 minutes at −78° C., a solution of 22.4 g (106.1 mmol) 5-bromo-3-methyl-1H-indazole in THF (300 ml) was added dropwise at such a rate that the temperature of the solution did not exceed −70° C. The mixture was stirred for 30 minutes before N,N-dimethylformamide (24.5 ml) was added dropwise. After 20 min, the cooling bath was removed, and stirring was continued for 1 h before water (250 ml) was added carefully. The mixture was extracted several times with ethyl acetate (500 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to yield 18.5 g of crude 3-methyl-1H-indazole-5-carbaldehyde, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[OH:10].C(N(CC)C(C)C)(C)C.Cl[CH2:21][O:22][CH3:23].Cl>ClCCl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:21][O:22][CH3:23]
Reactant: COCCl
Reactant: O=Cc1ccc(F)c(O)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cc(C=O)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Fluoro-3-hydroxybenzaldehyde (11.9 g) and N,N-diisopropylethylamine (44 mL) were dissolved in dichloromethane (100 mL). To the mixture was added chloromethylmethylether (13 mL), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added dropwise 1 mol/L hydrochloric acid (250 mL), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (14.5 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:14])=[O:7].[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17].N12CCCN=C1CCCCC2>O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][N:5]1[C:6](=[O:7])[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][C:16]1=[O:17]
Reactant: COC(=O)CNC(=O)c1ccncc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)Cn1c(=O)[nH]c2cnccc2c1=O
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of 100 mg of [(3-amino-pyridine-4-carbonyl)-amino]-acetic acid methyl ester in tetrahydrofuran (4.5 mL) is added 194 mg of 1,1′-carbonyldiimidazole and 0.18 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene at room temperature and the mixture is stirred at the same temperature for 2 h. Then the solvent is removed under vacuum and the residue is purified by flash chromatography on silica gel to give 100 mg (89%) of (2,4-dioxo-1,4-dihydro-2H-pyrido[3,4-d]pyrimidin-3-yl)-acetic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[C:9]1([C@@H:15]([NH2:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([NH:17][C@H:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:16])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: Fc1cccc(Br)n1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cccc(Br)n1)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 2-bromo-6-fluoropyridine (500 mg, 2.84 mmol) and (S)-(−)-1-phenylethylamine (0.435 mL, 3.41 mmol) were heated at 100° C. for 12 hours. The mixture was cooled to room temperature, dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 6% ethyl acetate-hexane) afforded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN([CH:20]=[O:21])C>>[F:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[C:7]=1[CH:20]=[O:21]
Reactant: COc1cc(F)cc(OC)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(F)c(C=O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a solution of 1-fluoro-3,5-dimethoxybenzene (3.12 g, 20.0 mmol) in DMF (15 mL) was added dropwise phosphoryl trichloride (1.55 mL) at 0° C. The reaction mixture was stirred at room temperature overnight and poured onto ice. The resulting mixture was extracted with ethyl acetate (2×50 mL) and the combined organic layers were dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/PE=1/8) to give the title compound as a yellow solid (2.75 g, Yield: 74.6%). 1H NMR (400 MHz, DMSO-d) δ 10.15 (s, 1H), 6.52-6.56 (m, 2H), 3.91 (s, 3H), 3.88 (s, 3H). MS (ESI) m/z=185 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11](O)[CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1>FC(F)(F)C(O)=O>[CH3:16][N:14]([CH3:15])[CH2:13][CH:12]=[CH:11][C:4]1[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=[C:2]([NH2:1])[CH:3]=1
Reactant: CN(C)CCC(O)c1cc(N)cc2c1OCC2
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC=Cc1cc(N)cc2c1OCC2
Yield: 105.7 %

Procedure:
A solution of 1-(5-amino-2,3-dihydrobenzofuran-7-yl)-3-dimethylaminopropan-1-ol (D 16) (2.12 g) in trifluoroacetic acid (60 ml) was refluxed for 10h, cooled and the solvent evaporated under reduced pressure. The residue was partitioned between 10% Na2CO3 and ethyl acetate, the organic phase was dried (Na2SO4) and the solvent evaporated under reduced pressure, to give the title compound as an orange foam (2.07 g, quantitative).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([CH:16]([NH:19][C:20]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[CH:25]3)=[O:21])[CH2:17][CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([N:27]1[C:28]2[C:24](=[CH:23][C:22]([C:20]([NH:19][CH:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:17][CH3:18])=[O:21])=[CH:30][CH:29]=2)[CH:25]=[CH:26]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC(NC(=O)c1ccc2[nH]ccc2c1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(NC(=O)c1ccc2c(ccn2C(=O)c2ccccc2)c1)c1ccccc1

Procedure:
Benzoyl chloride (1.1 equiv) was added to a solution of N-(1-phenylpropyl)-1H-indole-5-carboxamide in CH2Cl2, Et3N (1.3 equiv) at room temperature. After the reaction was completed, the solvent was evaporated and the residual was purified by silica gel column chromatography to get the product. LC-MS 383 (M+H).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:16])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[N+:12]([O-:14])=[O:13].C1C(=O)N([Br:24])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:11][C:7]1[C:6]([N+:12]([O-:14])=[O:13])=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([N:3]([O:2][CH3:1])[CH3:16])=[O:15]
Reactant: CON(C)C(=O)c1cccc(C)c1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CON(C)C(=O)c1cccc(CBr)c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of Intermediate 37A (5.5 g, 24.53 mmol), NBS (5.24 g, 29.4 mmol) and benzoyl peroxide (0.594 g, 2.453 mmol) in CCl4 (80 mL) was purged with nitrogen and then heated to 80° C. for 4.5 h. The reaction mixture was cooled to room temperature and then quenched with water. The mixture was extracted with DCM and the combined extracts were washed with saturated NaHCO3 and brine and then dried (Na2SO4), filtered and concentrated to dryness. The crude material was purified by flash chromatography (SiO2, 80 g column, EtOAc/hexane=0-100%) to afford Intermediate 37B.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[F:37][C:38]1([F:43])[CH2:42][CH2:41][NH:40][CH2:39]1>>[C:1]([C:3]1([NH:6][C:7]([CH:9]2[CH2:13][CH:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:40]4[CH2:41][CH2:42][C:38]([F:43])([F:37])[CH2:39]4)=[CH:19][C:18]=3[C:24]([F:25])([F:26])[F:27])(=[O:15])=[O:16])[CH2:11][CH:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: FC1(F)CCNC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Agent: Cl
Product: N#CC1(NC(=O)C2CC(S(=O)(=O)c3ccc(N4CCC(F)(F)C4)cc3C(F)(F)F)CC2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to Example 127 using (1R,2R,4R)-2-(3,3-Difluoro-azetidine-1-carbonyl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 118) and 3,3-difluoropyrrolidine hydrochloride. Off-white solid. MS (EI): 611.2 (M+H)+.