Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)=[O:49])=[CH:44][C:43]=1[CH3:55]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([C:48]([N:50]6[CH2:51][CH2:52][CH2:53][CH2:54]6)=[O:49])=[CH:44][C:43]=5[CH3:55])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1cc(C(=O)N2CCCC2)ccc1Br
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCCC4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (50 mg) and (4-bromo-3-methyl-phenyl)-pyrrolidin-1-yl-methanone (38 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-phenyl]-pyrrolidin-1-yl-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-267) as a pale yellow powder (7 mg, 16%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH:22](C)C)=[O:20])[CH:3]=1.NC1C(F)=C([Cl:33])N=C(C(OC)=O)C=1Cl>>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:33]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)cc(N)c2F)c1F
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)c(F)c(N)c1Cl

Procedure:
Methyl 4-(amino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-picolinate was prepared in analogous fashion to isopropyl 4-(amino)-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-picolinate in Example 10 except that methyl 4-amino-3,6-dichloro-5-fluoropicolinate was used in place of isopropyl 4-amino-6-bromo-5-fluoropicolinate: mp=169-171° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.46 (dd, J=8.8, 1.6 Hz, 1H), 7.29 (dd, J=8.8, 7.2 Hz, 1H), 7.10 (s, 2H), 3.93 (s, 3H), 3.87 (s, 3H); 13C NMR (100.6 MHz, DMSO-d6) δ 164.8, 154.3, 151.8, 146.2, 144.5, 143.9-143.7 (m), 141.6 (d, JF-C=14.0 Hz), 136.3 (d, JF-C=13.4 Hz), 128.5 (d, JF-C=2.6 Hz), 125.5 (d, JF-C=3.6 Hz), 122.9 (d, JF-C=13.7, 4.0 Hz), 61.6 (d, JF-C=4.2 Hz), 52.7; 19F {1H} NMR (376.5 MHz, DMSO-d6) δ −129.2 (d, JF-F=27.5 Hz), −137.7 (d, JF-F=27.1 Hz); IR: 3482, 3381, 2950, 1741, 1612, 1466, 1423, 1366, 1228, 1202, 1045, 970, 905, 815; MS Calcd. for C14H11Cl2F2N2O3: 362.0. Found: 362 (M+), 304.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: c1ccc2[nH]ccc2c1
Product: O=[N+]([O-])c1ccc(-n2ccc3ccccc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-4-nitrobenzene: ESMS m/e: 238.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:63][CH:64]1[CH2:68][CH2:67][NH:66][C:65]1=[O:69].[Al]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:13]1([C@H:11]2[CH2:12][C@H:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([N:66]5[CH2:67][CH2:68][CH:64]([CH3:63])[C:65]5=[O:69])[CH:20]=[CH:19][C:5]=4[N:6]=3)[CH2:10]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1CCNC1=O
Reactant: Brc1ccc2nc([C@H]3C[C@H](N4CCCCC4)C3)sc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC1CCN(c2ccc3nc([C@H]4C[C@H](N5CCCCC5)C4)sc3c2)C1=O
Temperature: 150 °C

Procedure:
To a microwave vial equipped with magnetic stir bar, 6-bromo-2-[trans-3-(piperidin-1-yl)cyclobutyl]-1,3-benzothiazole (3, 50 mg, 0.14 mmol) was added, Pd2(dba)3 (4.0 mg, 0.004 mmol), Xantphos (6.9 mg, 0.012 mmol) and CsCO3 (68 mg, 0.2 mmol), followed by 3-methylpyrrolidin-2-one (50 mg, 0.5 mmol). The reaction vial was then sealed with an aluminum cap, and placed under inert atmosphere by purging with N2. Dioxane (2 mL) was then introduced via a syringe. The reaction mixture was then subjected to sonication briefly to ensure mixing of the contents, and then heated in a commercial microwave oven at 150° C. for 60 min. The reaction mixture was cooled down to 23° C., and filtered to remove solids. The solvent was removed under vacuum, and from this, the residual mixture was purified by chromatography (SiO2, ethyl acetate (0-80%)/hexanes) to give the title compound as a pure product (28 mg, 55%). 1H NMR (300 MHz, CDCl3): δ=8.33 ppm (d, J=2.1 Hz, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.61 (dd, J=9.2, 2.1 Hz, 1H), 3.85 (m, 3H), 2.72 (m, 1H), 2.59 (m, 4H), 2.43 (m, 2H), 2.40 (m, 2H), 1.82 (m, 1H), 1.40-1.75 (m, 8H), 1.33 (d, J=7.1 Hz, 3H). MS (ESI, M+H+): 370.1.
Reaction SMILES: [C:1]([N:5]1[CH2:25][CH2:24][CH2:23][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([Br:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:26])([CH3:4])([CH3:3])[CH3:2].[Br:27]N1C(=O)CCC1=O>CN(C=O)C.O>[C:1]([N:5]1[CH2:25][CH2:24][CH2:23][C:8]2[C:9]([Br:27])=[C:10]3[C:19]4[CH:18]=[C:17]([Br:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2c(cc1Br)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1Br)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Reaction time: 0.25 h
Yield: 94 %

Procedure:
To a solution of 340 mg of 13b in 3 ml of DMF was added in small portions 160 mg of N-bromosuccinimide. After stirring for an additional 15 minutes the reaction mixture was diluted with 3 ml of water and stirred for an additional 15 minutes. The precipitate was filtered and dried, to give 380 mg of 13c, as white crystalline material. Mp: 218-220° C. MS-ESI: [M+1] 495.06, 497.06, 499.08. NMR (CDCl3) δ 1.53 (s, 9, tertC4H9), 1.95 (m, 2, CH2), 2.71 (t, 2, CH2), 2.97 (t, 2, CH2), 3.38 (t, 2, CH2), 4.45 (t, 2, CH2) 6.77, 8.56 (2×s, 2, Ar—H).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:10])=[C:5]([Br:9])[C:6]=1[C:7]#[N:8].CC(C)([O-])C.[K+].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].O>O1CCCC1>[Br:10][C:4]1[N:3]([C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[C:2]([Br:1])=[C:6]([C:7]#[N:8])[C:5]=1[Br:9]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(Br)c(Br)n(C(=O)Oc2ccccc2)c1Br

Procedure:
A mixture of 7.0 g of 2,4,5-tribromopyrrole-3-carbonitrile and 2.9 g of potassium t-butoxide in tetrahydrofuran is treated with 13.8 g of phenyl chloroformate, heated at reflux temperature for 12 hours, cooled, poured into water and filtered. The solid filter cake is washed with water and dried in vacuo to afford the title compound. A sample is recrystallized from a mixture of ethyl acetate and methylcyclohexane to give colorless crystals, mp 128° to 129° C.
Reaction SMILES: [Br:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CO.[BH4-].[Na+].Cl>C1COCC1>[Br:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:6][CH:7]=[CH:8][N:9]=1
Reactant: O=Cc1cccnc1Br
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cccnc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
To a mixture of 2-bromonicotinaldehyde (50 g, 0.27 mol), methanol (250 mL) and THF (250 mL) in a 3-necked round bottom flask at 0° C. was added sodium borohydride (10.3 g, 0.27 mol) portion wise. The reaction mixture was stirred at 0° C. for 1 hr and warmed up to room temperature. The reaction mixture was adjusted to pH 7 with 2N HCl (120 mL), and concentrated to remove methanol and THF. The resulting mixture was partitioned between EtOAc and brine three times. The organic layer was combined and washed with brine, dried over Na2SO4, and concentrated to give (2-bromopyridin-3-yl)methanol (51 g), which was used without further purification. LRMS (M+H+) m/z 187.9.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C@H:3]([N:30]1[CH2:34][CH2:33][C@H:32]([NH:35]C(=O)OC(C)(C)C)[CH2:31]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:24][C@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:17]=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.[ClH:45]>ClCCl.C(#N)C>[ClH:45].[ClH:45].[F:44][C:2]([F:1])([F:43])[C@H:3]([N:30]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:24][C@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:17]=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1
Reactant: COC[C@@H](C)Oc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Product: COC[C@@H](C)Oc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 792 %

Procedure:
To a solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-8-((R)-1-methoxypropan-2-yloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.12 g, 0.19 mmol) in dichloromethane (0.5 mL) was added hydrochloric acid (5-6M in 2-propanol; 9.5 mL, 0.61 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed under reduced pressure, and the solid obtained was suspended in acetonitrile (3 mL) and stirred at ambient temperature for 5 minutes. The solid formed was collected by vacuum filtration to give the title compound (0.89 g, 79%). LCMS APCI (+) m/z 519 (M+H). Specific rotation: [α]24D=2.44° (c=0.97, MeOH).
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]([CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[CH:11][C:12]=1[CH3:13])=[O:7])[CH3:4].C(O)C>CO.O>[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:11][C:12]=1[CH3:13])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1[nH]c(CCC(=O)OC(C)(C)C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]c(CCC(=O)O)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
Lithium hydroxide (1.02 g, 42.65 mmol) was added to a suspension of 5-(2-tert-butoxycarbonyl-ethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.4 g, 8.53 mmol) in methanol (50 mL) and water (12 mL). Ethanol (4 mL) was added to the mixture (to aid solvation of the starting material) and it was stirred at room temperature for overnight. The reaction was diluted with water (20 mL), concentrated (to remove most of the alcohol) and extracted with ether. The aqueous layer was the acidified to pH=2 using 1N HCl (43 mL) and extracted with ethyl acetate (2×). The combined extract was then washed with brine, dried and concentrated to give 1.89 g of 5-(2-carboxy-ethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.Cl.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36]N)=[CH:32][CH:31]=1>>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:33](=[CH:34][CH:35]=1)[NH:36][CH:2]=[C:6]2[CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][CH:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:26])[CH:23]([CH3:24])[CH3:25])[CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:14]1
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC3OCCO3)CC2)c1
Agent: Cl
Product: COc1ccc2[nH]cc(CCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[3-(1,3-dioxolan-2-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(4-methoxyphenyl)hydrazine hydrochloride: ESMS m/e: 420.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][OH:13])[CH:6]=1)=O.[C:14]([NH:17][C:18]([NH2:20])=[S:19])(=[O:16])[CH3:15]>O1CCCC1>[OH:13][CH2:12][CH2:11][C:7]1[CH:6]=[C:5]([C:3]2[N:20]=[C:18]([NH:17][C:14](=[O:16])[CH3:15])[S:19][CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(CCO)c1
Reactant: CC(=O)NC(N)=S
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(-c2cccc(CCO)c2)cs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a solution of 2-bromo-1-[3-(2-hydroxyethyl)phenyl]ethanone (crude, 658 mg) in tetrahydrofuran (15 ml) was added 1-acetyl-2-thiourea (320 mg) at 25° C. The mixture was stirred at 60° C. for 2 h. The residual colorless crystals were collected by filtration. The crystals were washed with isopropyl ether, dried under reduced pressure to give N-{4-[3-(2-hydroxyethyl)phenyl]-1,3-thiazol-2-yl}acetamide (514 mg) as a colorless crystal.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Br[C:26]1[CH:31]=[N:30][C:29]([I:32])=[CH:28][N:27]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[CH:31]=[N:30][C:29]([I:32])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Brc1cnc(I)cn1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2cnc(I)cn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-bromo-5-iodo-pyrazine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.51 min; Mass spectrum (ESI+): m/z=516 [M+H]+.
Reaction SMILES: [Cl-].C([N+]1(C)CCCC1)CCC.[CH:12]12[CH2:18][CH:15]([CH2:16][CH2:17]1)[CH:14]=[CH:13]2.[CH:19]([O:21][CH3:22])=[O:20]>[Ru].[Co]>[C:12]12([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][CH2:13]2
Reactant: C1=CC2CCC1C2
Reactant: COC=O
Agent: [Co]
Agent: [Ru]
Agent: CCCC[N+]1(C)CCCC1
Product: COC(=O)C12CCC(CC1)C2
Temperature: 120 °C

Procedure:
In a pressure reactor made of stainless steel and having an internal volume of 50 ml, 0.05 mmol of [Ru(CO)3Cl2]2 as a ruthenium compound, 0.05 mmol of Co2(CO)8 as a cobalt compound, and 0.25 mmol of butylmethylpyrrolidinium chloride as a halide salt were introduced and mixed at room temperature, and thus a catalyst system was obtained. 5.0 mmol of norbornene and 5.0 mL of methyl formate were added to this catalyst system, subsequently the reactor was purged with nitrogen gas at 0.5 MPa, and the system was maintained for 15 hours at 120° C. Thereafter, the reactor was cooled to room temperature, and the pressure was released. A portion of the remaining organic phase was withdrawn, and the components of the reaction mixture were analyzed by using gas chromatography. According to the analysis results, the amount of methyl norbornane monocarboxylate produced by the reaction was 7.07 mmol (yield in terms of norbornene 70.7%).
Reaction SMILES: [NH:1]([C:3](=[O:25])[C:4]([NH:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1)=[O:5])[NH2:2].[F:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=S)[CH:30]=[CH:31][C:32]=1[F:33].CCN=C=NCCCN(C)C.[OH-].[Na+].Cl>CN(C=O)C.CO.C1COCC1.O>[F:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[O:25][C:3]([C:4]([NH:6][C:7]3[CH:8]=[CH:9][C:10]([O:11][C@@H:12]4[CH2:13][CH2:14][C@H:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]4)=[CH:23][CH:24]=3)=[O:5])=[N:1][N:2]=2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: Fc1ccc(N=C=S)cc1F
Reactant: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(NC(=O)C(=O)NN)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(O[C@H]2CC[C@@H](C(=O)O)CC2)cc1)c1nnc(Nc2ccc(F)c(F)c2)o1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
Ethyl cis-4-(4-{[hydrazino(oxo)acetyl]amino}phenoxy)cyclohexanecarboxylate (Intermediate 1, 698 mg, 2.00 mmol) was added in one portion to a stirred solution of 3,4-difluorophenyl isothiocyanate (411 mg, 2.40 mmol) in DMF (10 mL) and the reaction mixture was stirred at 65° C. for 30 mins. EDCI (461 mg, 2.40 mmol) was added in one portion and the reaction mixture was heated to 85° C. for 3 h. The mixture was cooled to ambient temperature and water (15 mL) was added and the resulting suspension was filtered to leave a cream solid. The solid was taken up in a mixture of MeOH (8 mL) and THF (4 mL) and a 2N aqueous solution of NaOH (4 mL) was added in one portion and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was acidified by the addition of 2M HCl and the resulting precipitate was filtered, washed with water (10 mL) and dried under high vacuum to leave a solid. The solid was recrystallised from refluxing glacial acetic acid to give the title compound as a white solid (428 mg, 47%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=4)[CH:20]=3)[N:15](S(C3C=CC(C)=CC=3)(=O)=O)[CH:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O.C1COCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=4)[CH:20]=3)[NH:15][CH:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5ccccc5)c4)c3c2)c1
Yield: 9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(3-(3-(1-benzyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methanesulfonamide (60 mg, 0.1 mmol) was hydrolyzed by lithium hydroxide (9 mg, 0.2 mmol) in methanol/water/THF (1/1/1 ml) which afforded 4 mg (9% yield) after purification by preparative TLC (silicagel-1000 micron) using 5% methanol in chloroform as eluent. 1H NMR (DMSO-d6, 300 MHz): δ 8.46-8.45 (d, 1H), 8.34-8.33 (d, 1H), 8.14 (s, 1H), 7.9 (s, 1H), 7.62 (s, 1H), 7.54 (m, 1H), 7.5-7.43 (m, 2H), 7.37-7.33 (m, 2H), 7.3-7.27 (m, 3H), 5.4 (s, 2H), 3.0 (s, 3H). MS: m/z=443.6 (M+1), HPLC: 88.2%, Method A.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[NH:21]([CH3:45])[C@H:22]([C:26]([NH:28][C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24].O>C1COCC1>[NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([N:21]([CH3:45])[C@H:22]([C:26]([NH:28][C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:39])([CH3:41])[CH3:40])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Reactant: CN[C@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of Boc-Phe(4-F)-OH (890 mg, 3.14 mmol), N-Me-Val-Tyr(3-tBu)-NH2 (1 g, 2.86 mmol) and CMPI (804 mg, 3.15 mmol) in THF (20 ml), TEA (1.2 ml, 7.16 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: acetone:n-hexane=1:2), giving Boc-Phe(4-F)-N-Me-Val-Tyr(3-tBu)-NH2 (1.5 g, 85%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:49][NH:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:51]([N:50]([CH3:49])[C:23]([C:18]1[NH:19][C:20]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:12]([N:9]1[CH2:8][CH2:7][N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:11][CH2:10]1)=[O:13])=[CH:22][CH:21]=2)=[O:25])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: CNCc1ccccc1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), methylbenzylamine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])C(=O)OC.COC(=O)N(CCC1C=CC(N)=C(CS(C2C=CC=CC=2)(=O)=O)C=1)C>>[CH3:1][NH:2][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: COC(=O)N(C)CCc1ccc2[nH]nc(S(=O)(=O)c3ccccc3)c2c1
Agent: COC(=O)N(C)CCc1ccc(N)c(CS(=O)(=O)c2ccccc2)c1
Product: CNCCc1ccc2[nH]nc(S(=O)(=O)c3ccccc3)c2c1

Procedure:
Methyl methyl{2-[3-(phenylsulfonyl)-1H-indazol-5-yl]ethyl}carbamate Using substantially the same procedure described in Example 171, step 3 and employing methyl(2-{4-amino-3-[(phenylsulfonyl)methyl]phenyl}ethyl)methylcarbamate (0.362 g, 1 mmol), the title compound was obtained as a white solid, (0.29 g, 78%). Mp: 145-147° C., MS (ES+): 374 (M+H)+ Step 6