Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:41])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][O:33]C3CCCCO3)[CH:27]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][OH:33])[CH:27]=4)[CH:21]=3)[CH2:18][C:17](=[O:41])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-methyl-2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M259) (0.50 g, 0.84 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (182 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[C:7]([CH2:18][NH:19][C:20]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>>[CH2:34]([O:33][C:31]([N:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:20]([NH:19][CH2:18][C:7]2[C:6](=[O:29])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:8]=2)=[O:21])[CH2:24][CH2:25]1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)NC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
4-[3-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-ureido]-piperidine-1-carboxylic acid benzyl ester was prepared starting from intermediate N and benzyl chloroformate MS calcd. for C30H30ClN4O4 [(M+H)+] 545.2, obsd. 545.0.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([OH:17])=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:18][CH2:19][CH3:20].I[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1>>[CH3:1][CH:2]([CH3:21])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([O:17][CH2:23][CH2:24][CH:25]4[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:29][CH2:30]4)=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:18][CH2:19][CH3:20]
Reactant: CCCc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Product: CCCc1nc2cnc3cc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c2n1CC(C)C

Procedure:
The general method described in Part L of Example 2 was used to treat 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol with tert-butyl 4-(2-iodoethyl)piperidine-1-carboxylate. After the work-up procedure, tert-butyl 4-(2-{[1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)piperidine-1-carboxylate was isolated as a gray-brown solid and used without purification.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[N:10]=1.[C:11]([NH:30][C:31]1[S:32][CH:33]=[C:34](/[C:36](=[N:63]/[O:64][CH3:65])/[C:37]([NH:39][CH:40]2[C:61](=[O:62])[N:42]3[C:43]([C:49]([O:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=4)=[O:50])=[C:44]([CH2:47]Cl)[CH2:45][S:46][C@H:41]23)=[O:38])[N:35]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([NH:30][C:31]1[S:32][CH:33]=[C:34](/[C:36](=[N:63]/[O:64][CH3:65])/[C:37]([NH:39][CH:40]2[C:61](=[O:62])[N:42]3[C:43]([C:49]([O:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=4)=[O:50])=[C:44]([CH2:47][S:1][C:2]4[S:3][C:4]5[CH:5]=[N:6][CH:7]=[CH:8][C:9]=5[N:10]=4)[CH2:45][S:46][C@H:41]23)=[O:38])[N:35]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Sc1nc2ccncc2s1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(CSc3nc4ccncc4s3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 67 %

Procedure:
Using 60 mg of 2-mercaptothiazolo[5,4-c]pyridine in place of 2-mercaptothiazolo[4,5-c]pyridine and 238 mg of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 186 mg of the title compound in a yield of 67%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[OH-].[Na+].[O-:27]S([O-])(=S)=O.[Na+].[Na+].C(O)(=O)C>CO.O.OO>[CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:6][CH:5]=[N:4][C:3]=1[CH2:14][S+:15]([O-:27])[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
2 g of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazole was suspended in 36 ml of methanol at room temperature, to which 1.76 g of 45% NaOH in 14 ml water was added while stirring. 0.09 g of Na2WO4·2H2O oxidation catalyst was dissolved in 0.77 g H2O2 (50% aqueous solution), and further diluted with 10 ml of water. The oxidant/catalyst solution was added to the reactant/base solution dropwise so that the addition was completed in about 30 minutes while stirring at room temperature. The reaction was continued for additional 10 minutes while stirring. 10 ml of 10% Na2S2O3 aqueous solution was then added, and the resulting mixture was subjected to a reduced pressure to remove methanol therefrom. Finally, a precipitate was formed after adding a diluted acetic acid aqueous solution to a pH value of about 8, which was filtered, water washed, and dried in vacuo to obtain Lansoprazole with a yield of about 90.8% (LC purity>95%).
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:17]1[O:27][C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[O:19][CH2:18]1.[NH4+].[Cl-]>C1COCC1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:23]2([OH:26])[CH2:24][CH2:25][C:20]3([O:27][CH2:17][CH2:18][O:19]3)[CH2:21][CH2:22]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc(OCc3ccccc3)cc2)CCC2(CC1)OCCO2
Yield: 80.3 %

Procedure:
To a solution of the Grignard reagent prepared from Magnesium turnings (2.33 g, 96 mmol) and 4-benzyloxybromobenzene (25 g, 95 mmol) in THF (150 ml), 1,4-Cyclohexanedione monoethylene ketal (10 g, 64 mmol) in THF (150 ml) was added. After completeion of the reaction, the solution was added to 200 ml of aq. NH4Cl and extracted with CH2Cl2. Drying and evaporation of the organic layer gave a residue which was crystallised from AcOEt-hexane to give 8-(4-benzyloxy-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (17.5 g, 54%, MS: m/e=340 (M+)).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([C@H:12]([C:18]([OH:20])=O)[CH2:13][CH2:14][C:15]([NH2:17])=[O:16])[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C1C=CN=CC=1.O1CCCC1>[CH:2]1[CH:1]=[CH:6][C:5]2[C:7](=[O:8])[N:9]([CH:12]3[C:18](=[O:20])[NH:17][C:15](=[O:16])[CH2:14][CH2:13]3)[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: NC(=O)CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1
Yield: 90 %

Procedure:
A stirred mixture of N-phthaloyl-L-glutamine (48.0 g, 174 mmoL), carbonyldiimidazole (30.43 g, 188 mmoL), and 4-dimethylaminopyridine (0.105 g, 0.861 mmoL) in anhydrous tetrahydrofuran (300 mL) is heated to reflux for 16 hours. The reaction slurry is filtered and the solid washed with methylene chloride (200 mL). The solid is air-dried and then dried in vacuo (60° C., <1 mm) to afford 40.40 g (90%) of thalidomide as a white powder. 1HNMR (DMSO-d6) δ 11.16 (s, 1 H, NH), 8.05-7.80 (br s, 4 H, Ar), 5.18 (dd, 1 H, J=12, 5 Hz, CHCO), 3.05-2.85 (m, 1 H, CH2CO), 2,70-2.45 (m, 2 H, CH2CH 2), 2.15-2.00 (M, 1 H, CH2). 13C NMR (DMSO-d6) δ 172.8, 169.8, 167.1, 134.9, 131.2, 123.4, 49.0, 30.9, 22.0.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[F:20].[C:21]([O:40][CH2:41][C@@H:42]1[C@@H:49]2[C:45](=[N:46][O:47][CH2:48]2)[CH2:44][O:43]1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1.C1COCC1.COC(C)(C)C.O>[F:20][C:14]1[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=1[C@:45]12[CH2:44][O:43][C@H:42]([CH2:41][O:40][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:49]1[CH2:48][O:47][NH:46]2
Reactant: c1ccc(C(OC[C@H]2OCC3=NOC[C@@H]32)(c2ccccc2)c2ccccc2)cc1
Reactant: Fc1cccc(Br)c1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: Fc1cccc([C@]23CO[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]2CON3)c1F
Temperature: -75 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
A 2.50 M solution of n-butyllithium in hexane (197 mL, 0.493 mol, 1.90 equiv.) was added dropwise to a solution containing 1-bromo-2,3-difluorobenzene (95.1 g, 0.493 mol, 1.90 equiv.) in THF/toluene (100 mL/1000 mL) under a nitrogen atmosphere at −75 to −69° C. After 10 min, boron trifluoride-diethyl etherate complex (62.5 mL, 0.493 mol) was added dropwise while maintaining temperature below −71° C. A previously prepared solution of (3aR*,4S*)-4-((trityloxy)methyl)-3,3a,4,6-tetrahydrofuro[3,4-c]isoxazole (100 g, 0.259 mol, 1.0 equiv.) in THF (400 mL) was added while maintaining the temperature below −70° C. After stirring at the −75° C. for 1.5 h, saturated aq. NH4Cl (300 mL) and water (100 mL) were slowly added (over 5 min) to the reaction solution. 2-methoxy-2-methylpropane (300 mL) was added and the reaction was allowed to warm up to 0° C. The organic phase was isolated and washed with 27% aq NaCl solution (200 mL). The organic layer concentrated under reduced pressure and recrystallised from THF (200 mL)/isopropyl alcohol (700 mL). Title compound (87.5 g) was isolated. 1H NMR (500 MHz, DMSO) δ ppm 7.42-7.33 (m, 8H), 7.31 (t, J=7.6 Hz, 6H), 7.28-7.21 (m, 3H), 7.20-7.12 (m, 1H), 6.39 (s, 1H), 4.13 (d, J=8.2 Hz, 1H), 4.03 (s, 1H), 3.97 (s, 1H), 3.89 (d, J=9.2 Hz, 1H), 3.81-3.70 (m, 1H), 3.36-3.29 (m, 1H), 3.26 (dd, J=10.1, 6.0 Hz, 1H), 3.15 (dd, J=10.0, 3.5 Hz, 1H); 13C NMR (125 MHz, DMSO) δ ppm 150.74 (dd, JCF=246.4, 14.4 Hz), 148.66 (dd, JCF=248.3, 13.5 Hz), 144.09, 130.58, 128.67, 128.32, 127.48, 124.75, 124.45, 117.18 (d, JCF=17.0 Hz), 86.57, 84.91, 78.16, 76.81, 64.82, 56.46.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[N:8][C:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.[CH2:20](I)[CH3:21]>O1CCCC1>[CH2:20]([N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:7]2[N:8]=[N:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[CH:11]=1)[C:17](=[O:19])[CH3:18])[CH3:21]
Reactant: CC(=O)Nc1cccc(-c2ccc(Cl)nn2)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(C)=O)c1cccc(-c2ccc(Cl)nn2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 4.0 g of sodium hydride (50% dispersion in oil) in 400 ml of anhydrous tetrahydrofuran was added 18.0 g of N-[3-(6-chloro-3-pyridazinyl)phenyl]acetamide. The solution was stirred (or 0.5 hrs, then 6.4 ml ethyl iodide was added. After stirring for 18 hours the reaction mixture was treated as described in Example 63 to give 19.8 g of colorless crystals, mp 116°-119° C. Recrystallization from acetone-hexane gave colorless crystals, mp 120°-121° C.
Reaction SMILES: [CH2:1]([C:4]1[C:17]([Br:18])=[CH:16][C:15]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:14]([Cl:28])[C:5]=1[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH:2]=[CH2:3].CSC.B.[OH-:33].[Na+].OO>C1COCC1.O>[Br:18][C:17]1[C:4]([CH2:1][CH2:2][CH2:3][OH:33])=[C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:9])[C:14]([Cl:28])=[C:15]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH:16]=1
Reactant: [OH-]
Reactant: C=CCc1c(Br)cc(Cc2ccc(OC)cc2)c(Cl)c1O[Si](C)(C)C(C)(C)C
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CSC
Product: COc1ccc(Cc2cc(Br)c(CCCO)c(O[Si](C)(C)C(C)(C)C)c2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of bromide 186 (2.57 g, 5.33 mmol) in THF (35 mL) was added borane dimethylsulfide complex (10M in THF, 0.18 mL, 1.76 mmol) at 0° C. The mixture was stirred at rt for 1 hr. The mixture was cooled to 0° C. and H2O (0.5 mL), aq. 3N NaOH solution (1.1 mL), 35% H2O2 (0.65 mL) were added to the mixture.) The mixture was stirred at 50° C. for 30 min and cooled to rt. The mixture was extracted with EtOAc/aq. 50% NaCl solution (100 mL/100 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 187 (1.73 g, 65%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[F:33][C:34]([F:44])([F:43])[C:35]1[NH:39][C:38]([C@@H:40]([NH2:42])[CH3:41])=[N:37][CH:36]=1.C(N(C(C)C)CC)(C)C.C1CN(C(ON2N=NC3C2=CC=CC=3)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl.O>[F:44][C:34]([F:33])([F:43])[C:35]1[NH:39][C:38]([C@@H:40]([NH:42][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=2)=[O:22])[CH3:41])=[N:37][CH:36]=1
Reactant: C[C@H](N)c1ncc(C(F)(F)F)[nH]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2OC(N1CCCC1)=[N+]1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ncc(C(F)(F)F)[nH]1
Yield: 62.3 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (40 mg, 90.6 μmol), (S)-1-(5-(trifluoromethyl)-1H-imidazol-2-yl)ethanamine hydrochloride (32.5 mg, 151 μmol), diisopropylethylamine (63.3 μL, 362 μmol) in DMF (2 mL) was added o-(benzotriazol-1-yl)-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate (43.0 mg, 99.7 μmol). After 15 hours the reaction mixture was diluted with dichloromethane and water. The organic layer was washed with saturated sodium carbonate and brine then dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by chromatography (silica, 12 g Analogix column, 50-70% ethyl acetate in hexanes, gradient over 30 min) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(S)-1-(5-trifluoromethyl-1H-imidazol-2-yl)-ethyl]-amide (34 mg, 62%) as a light yellow solid. LCMS, [M+H]=603.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.[H-].[Na+].CC1C=CC(S(O[CH:35]2[CH2:40][CH2:39][CH:38]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH2:37][CH2:36]2)(=O)=O)=CC=1>CN(C=O)C>[Si:42]([O:41][CH:38]1[CH2:37][CH2:36][CH:35]([N:11]2[C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=3[C:9]([C:12]3[CH:13]=[CH:14][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:16][CH:17]=3)=[N:10]2)[CH2:40][CH2:39]1)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]
Reactant: COc1nccc2[nH]nc(-c3ccc(S(N)(=O)=O)cc3)c12
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(O[Si](C)(C)C(C)(C)C)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To a solution of 4-(4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (50.0 mg) obtained in Step A of Example 100 in DMF (2 mL) was added sodium hydride (60% dispersion in mineral oil, 7.89 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 4-((tert-butyl(dimethyl)silyl)oxy)cyclohexyl 4-methylbenzenesulfonate (76.0 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (52.8 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[S:7][C:6]=2[CH:13]=1.[C:14]([C@@H:16]1[CH2:18][C@H:17]1[CH2:19][OH:20])#[CH:15].C(N(CC)CC)C>CN(C=O)C.[Cu]I.[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[OH:20][CH2:19][C@@H:17]1[CH2:18][C@H:16]1[C:14]#[C:15][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[S:7][C:6]=2[CH:13]=1
Reactant: C#C[C@@H]1C[C@H]1CO
Reactant: O=C(O)c1cc2ccc(Br)cc2s1
Agent: [Cu]I
Agent: [Pd+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cc2ccc(C#C[C@@H]3C[C@H]3CO)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a stirring solution of 6-bromobenzo[b]thiophene-2-carboxylic acid (7.1, 1.0 g, 3.9 mmol) in DMF (7.5 mL) under a nitrogen atmosphere were added racemic ((trans)-2-ethynylcyclopropyl)methanol (1.7, 935 mg, 9.7 mmol), copper(I) iodide (30 mg, 0.16 mmol) and palladium(II) bis(triphenylphosphine)dichloride (56 mg, 0.08 mmol), followed by triethylamine (2.5 mL) and the reaction was stirred at room temperature for 1 hr, and then at 40° C. for 20 hr. The reaction mixture was partitioned between 2N aqueous sodium hydroxide and ethyl acetate. The aqueous layer was acidified with conc HCl and extracted with ethyl acetate. The resulting organic layer was washed with water, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 6-(((trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)benzo[b]thiophene-2-carboxylic acid (7.2, 900 mg, 3.3 mmol, 85%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH2:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].FC(F)(F)[C:25]1([CH:40]=[CH:39][CH:38]=[CH:37][CH2:36]1)[O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=1>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH:21][C:31](=[O:33])[C:30]1[CH:29]=[CH:28][C:27]([O:26][C:25]2[CH:36]=[CH:37][C:38]([C:17]([F:20])([F:19])[F:18])=[CH:39][CH:40]=2)=[CH:35][CH:34]=1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(OC2(C(F)(F)F)C=CC=CC2)cc1
Reactant: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(C(F)(F)F)cc1
Product: CC(=O)OCCNC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)NC(=O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
A reaction similar to that described in Example 50 was conducted using 2-({(2S)-2-amino-3-[4-(trifluoromethyl)phenyl]propanoyl}amino)ethyl acetate and 4-[1-(trifluoromethyl)phenoxy]benzoic acid used in Example 41 (41a) to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]([OH:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([OH:24])=[O:23])([C:18]([OH:20])=[O:19])[OH:17].[F:27][C:28]1[CH:29]=[C:30]([CH:35]([CH2:54][CH2:55]N2CCC(C3C=CC=CC=3[S@](C)=O)CC2)[CH2:36][N:37]([CH3:53])[C:38]([C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=[C:42]([N+:50]([O-:52])=[O:51])[CH:41]=2)=[O:39])[CH:31]=[CH:32][C:33]=1[F:34]>O>[C:14]([OH:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([OH:24])=[O:23])([C:18]([OH:20])=[O:19])[OH:17].[F:27][C:28]1[CH:29]=[C:30]([CH:35]([CH2:54][CH2:55][N:11]2[CH2:12][CH2:13][CH:8]([N:3]3[CH2:4][CH2:5][CH2:6][NH:7][C:2]3=[O:1])[CH2:9][CH2:10]2)[CH2:36][N:37]([CH3:53])[C:38]([C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=[C:42]([N+:50]([O-:52])=[O:51])[CH:41]=2)=[O:39])[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: CN(CC(CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(F)c(F)c1)C(=O)c1cc([N+](=O)[O-])cc2ccccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Product: CN(CC(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(F)c(F)c1)C(=O)c1cc([N+](=O)[O-])cc2ccccc12

Procedure:
Using standard reductive amination conditions 4-(tetrahydro-2-oxo-1(2H)-pyrimidinyl)piperidine (Miller, S C; Jacobs, R T; Shenvi, A B. EP 739891) was reacted with N-[2-(3,4-difluorophenyl)-4-oxobutyl]-N-methyl-3-nitro-1-naphthamide [Example 13] and converted to the citrate salt. MS m/z 580 (M+H); analysis for C31H35F2N5O4.1.07 C6H8O7.1.06 H2O: calculated: C, 55.88; H, 5.72; N, 8.71. found: C, 55.94; H, 5.54; N 8.51.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:4]=2[CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH:53]1[CH2:58][CH2:57][CH:56]([C:59]2[C:60](=[O:69])[NH:61][C:62]3[C:67]([CH:68]=2)=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH2:55][CH2:54]1>CN(C)C=O>[Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:19])[N:53]3[CH2:54][CH2:55][CH:56]([C:59]4[C:60](=[O:69])[NH:61][C:62]5[C:67]([CH:68]=4)=[CH:66][CH:65]=[CH:64][CH:63]=5)[CH2:57][CH2:58]3)[CH2:15][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2COC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OCc2c(cc(Br)c3[nH]ncc23)C[C@H]1CC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
(S)-2-(4-Bromo-8-oxo-6,7,8,10-tetrahydro-3H-oxepino[3,4-e]indazol-7-yl)acetic acid (90 mg, 0.265 mmol) was dissolved in N,N-dimethylformamide (2.5 mL). N,N-Diisopropylethylamine (150 μl, 0.861 mmol) was added to the mixture followed by TBTU (94.5 mg, 0.294 mmol). 3-(Piperidin-4-yl)quinolin-2(1H)-one hydrochloride (90.3 mg, 0.341 mmol) was added to the reaction mixture. Reaction stirred at room temperature for 3 hours. Reaction was quenched with water. Material was extracted twice with ethyl acetate. Organic phase was filtered. Filtrate was concentrated by roto-vap. Residue was purified by prep HPLC (acetonitrile-water-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 19% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.98 (s, 1H) 12.21 (s, 1H) 8.86 (s, 1H) 8.13 (d, J=3.36 Hz, 1H) 8.05 (t, J=6.87 Hz, 1H) 7.81-7.93 (m, 2H) 7.70 (d, J=8.24 Hz, 1H) 7.57 (t, J=7.63 Hz, 1H) 6.38 (d, J=14.65 Hz, 1H) 6.00 (d, J=14.95 Hz, 1H) 4.98 (d, J=13.12 Hz, 1H) 4.48-4.56 (m, 2H) 3.67-3.74 (m, 1H) 3.54-3.67 (m, 1H) 3.30-3.53 (m, 3H) 3.04-3.16 (m, 1H) 2.95-3.04 (m, 1H) 2.36 (t, J=11.14 Hz, 1H) 2.28 (t, J=9.46 Hz, 1H) 1.91-2.04 (m, 1H) 1.77-1.90 (m, 1H). High resolution M/E (M+H)+=549.1132.