Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].CSC.C(S)(S)C>>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[F:39][C:40]([C:41]([OH:43])=[O:42])([F:45])[F:44]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(N)=O
Agent: CC(S)S
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(N)=O
Yield: 100 %

Procedure:
Condensation of BocDTrpOPFP (4.70 g.) and HLeu-MetNH2 hydrochloride salt (Example 1, 2.98 g.) by the activated ester method using ethyldiisopropylamine gave BocDTrp-Leu-MetNH2 in 71% yield. De-t-butoxycarbonylation of BocDTrp-Leu-MetNH2 using trifluoroacetic acid, methyl sulfide, and ethanedithiol gave HDTrp-Leu-MetNH2 trifluoroacetate salt in 100% yield. Condensation of BocD,LBpaOH (2.95 g.) and HDTrp-Leu-MetNH2 trifluoroacetate salt (3.79 g.) by the mixed anhydride method using diphenylphosphinyl chloride and separation of the diastereoisomers by column chromatography on silica gel using chloroform-methanol (91:9) as eluant gave BocLBpa-DTrp-Leu-MetNH2 and BocDBpa-DTrp-Leu-MetNH2 each in 19% yield. De-t-butoxycarbonylation of BocLBpa-DTrp-Leu-MetNH2 (0.875 g.) and BocLBpa-DTrp-Leu-MetNH2 (0.875 g.) using trifluroracetic acid in methyl ethyl sulfide and ethanedithiol gave HLBpa-DTrp-Leu-MetNH2 and HDBpa-DTrp-Leu-MetNH2, both as the trifluoroacetate salts and both in 100% yield.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]#[C:12][C@@H:13]2[O:15][C@H:14]2[CH:16]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19]>C1C=CC=CC=1>[C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]#[C:12][C@@H:13]2[O:15][C@H:14]2[CH:16]=[CH:20][CH:18]=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Solvent: c1ccccc1
Product: O=CC=C[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Temperature: 70 °C
Yield: 51.9 %

Procedure:
(trans)-3-(6-Phenyl-1,3,5-hexatriynyl)oxiranecarboxaldehyde (80 mg, 0.36 mmole; see Example 4) and formylmethylenetriphenylphosphorane (122 mg, 0.40 mmole) were dissolved in 10 ml of dry benzene and the mixture was heated at 70° C. for 10 minutes. The mixture was then cooled to room temperature and the solvent was removed in vacuo. The residue was taken up in ether and filtered through a plug of silica gel. Removal of solvent afforded a brown oil which was purified by chromatography (silica gel, ether-hexane 1:1) to afford 46 mg of the title compound, melting point 91°-92.5° C.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]([CH2:30][CH2:31][NH2:32])[C:15]2[C:20]([N:21]=1)=[C:19]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[N:18]=[C:17]([CH3:29])[N:16]=2.N1C=CC=CC=1>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]([CH2:30][CH2:31][NH:32][C:2](=[O:3])[O:4][CH3:5])[C:15]2[C:20]([N:21]=1)=[C:19]([N:22]1[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]1)[N:18]=[C:17]([CH3:29])[N:16]=2
Reactant: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Cl)n(CCN)c2n1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)NCCn1c(-c2ccccc2Cl)nc2c(N3CCN(C)CC3)nc(C)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
Add methyl chloroformate (0.25 g, 0.0027 mol) to a solution of 2-[8-(2-chlorophenyl)-2-methyl-6-(4-methylpiperazin-1-yl)purin-9-yl]ethanamine (0.39 g, 0.0010 mol) and pyridine (4.0 mL) in dry dichloromethane (4 mL) at 0° C. Allow to warm to room temperature and stir for 2 hour. Quench the reaction mixture with saturated aqueous sodium bicarbonate solution and then extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column using dichloromethane:methanol (97:3) as eluent to afford methyl N-[2-[8-(2-chlorophenyl)-2-methyl-6-(4-methylpiperazin-1-yl)purin-9-yl]ethyl]carbamate (0.3 g). ES/MS m/z 444 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C:5]1[CH:18]=[C:17]([O:19]CC2C=CC=CC=2)[C:8]2[N:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4].C(O)(=O)C>C(O)C.O1CCCC1.[Pd]>[CH3:1][N:2]([CH3:27])[C:3]([C:5]1[CH:18]=[C:17]([OH:19])[C:8]2[N:9]=[C:10]([C:13]([F:16])([F:14])[F:15])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc(OCc2ccccc2)c2nc(C(F)(F)F)n(C)c2c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(O)c2nc(C(F)(F)F)n(C)c2c1
Yield: 100.9 %

Procedure:
A solution of 9.0 g (23.8 mmol) 7-benzyloxy-3-methyl-2-trifluoromethyl-3H-benzimidazole-5-carboxylic acid dimethylamide and 1.2 ml acetic acid in 300 ml ethanol-tetrahydrofuran (1:1) was hydrogenated over 1.1 g 10% Pd/C in autoclave (5 bar H2) at 50° C. for 16 h. The catalyst was filtered off and the filtrate concentrated in vacuo to afford 6.9 g (100%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[O:32])=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: CN1CCN(C(=O)CCl)CC1
Product: CN1CCN(C(=O)Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3cc(F)ccc34)c3ccc(Cl)cc32)CC1

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (the preparation of which have been described in example 19) with commercially available 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone as electrophile, the title compound was obtained as a white solid. ES-MS m/e (%): 539.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:8]=2[C:9]2[C:10]([CH2:23][O:24][CH3:25])=[C:11]([C:20](O)=[O:21])[N:12]=[CH:13][C:14]=2[NH:15]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:40](=[N:44]O)([NH2:43])[CH2:41][CH3:42]>CN(C)C=O>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:8]=2[C:9]2[C:10]([CH2:23][O:24][CH3:25])=[C:11]([C:20]4[O:21][N:44]=[C:40]([CH2:41][CH3:42])[N:43]=4)[N:12]=[CH:13][C:14]=2[NH:15]3)=[CH:4][CH:3]=1
Reactant: COCc1c(C(=O)O)ncc2[nH]c3cccc(Oc4ccc(Cl)cc4)c3c12
Reactant: CCC(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCc1noc(-c2ncc3[nH]c4cccc(Oc5ccc(Cl)cc5)c4c3c2COC)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.74 g of 5-(4-chlorophenoxy)-4-methoxymethyl-beta-carboline-3-carboxylic acid are dissolved in 150 ml of absolute dimethylformamide, mixed with 2.91 g of carbonyldiimidazole and stirred for 3 hours at room temperature. To this solution is added 3.96 g of propionamidoxime, it is stirred for 8 hours, 1 g of propionamidoxime is added once more and also stirred for 8 hours. After evaporation on the oil pump vacuum, it is taken up in toluene and refluxed for 8 hours. After evaporation, it is chromatographed twice over silica gel, first with methylene chloride/ethanol=10:1 and then with hexane: acetone=1:1 as eluant. After recrystallization from ethyl acetate/hexane and drying over phosphorus pentoxide at 80° C. in a vacuum, 2.2 g of 5-(4-chlorophenoxy-3-(3-ethyl-1,2,4-oxadizaol-5-yl)-4-methoxymethyl-beta-carboline with a melting point of 170° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:25]=[CH:24][C:19]([C:20]([NH:22][CH3:23])=[O:21])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:28])[CH:3]=1.[CH3:29][N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36](O)=[O:37])[C:31]1=[O:39]>>[F:28][C:4]1[CH:3]=[C:2]([NH:1][C:36]([C:32]2[C:31](=[O:39])[N:30]([CH3:29])[CH:35]=[CH:34][CH:33]=2)=[O:37])[CH:27]=[CH:26][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20](=[O:21])[NH:22][CH3:23])=[CH:18][CH:17]=3)[S:15][C:8]=12
Reactant: Cn1cccc(C(=O)O)c1=O
Reactant: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Product: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)c5cccn(C)c5=O)cc4F)c3s2)cc1
Yield: 30 %

Procedure:
Prepared from 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-N-methylbenzamide (Example 95, Step A) and 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (3% MeOH in CH2Cl2) to afford 11.1 mg (30%) of the desired product. LRMS (ESI pos) m/e 529.2 (M+1). 1H NMR (400 MHz, CDCl3/CD3OD) δ 8.59 (dd, 1H), 8.46 (d, 1H), 8.01 (dd, 1H), 7.94 (m, 2H), 7.88 (m, 3H), 7.67 (s, 1H), 7.47 (m, 1H), 7.36 (t, 1H), 6.64 (m, 2H), 3.75 (s, 3H), 2.98 (s, 3H); 19F NMR (376 MHz, CDCl3/CD3OD) 6-128.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:30]=[CH:29][C:9]2[O:10][C:11]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=3)[O:12][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[F:28][C:23]1[CH:22]=[C:21]([C:11]2([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=3)[O:10][C:9]3[CH:29]=[CH:30][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=3[O:12]2)[CH:26]=[C:25]([F:27])[CH:24]=1
Reactant: CCOC(=O)c1ccc2c(c1)OC(c1cc(F)cc(F)c1)(c1cc(F)cc(F)c1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)OC(c1cc(F)cc(F)c1)(c1cc(F)cc(F)c1)O2
Yield: 81.9 %

Procedure:
267 mg 2,2-bis-(3,5-difluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid ethyl ester, 3.8 mL ethyl alcohol and 0.96 mL 1N NaOH were stirred at room temperature for 6 h. The solvent was evaporated and the residue worked up with ethyl acetate, diluted hydrochloric acid and water. Purification on silica gel afforded 204 mg white crystals, m.p.: 96° C.; MS: 389 ([M−H]−).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[C:18]([Br:25])[N:17]=2)=[O:15])=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].Cl>CO.O>[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[C:18]([Br:25])[N:17]=2)=[O:15])=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(C(=O)c2nc(Br)c3ccccn23)ccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(C(=O)c2nc(Br)c3ccccn23)cc1C(=O)O
Yield: 98 %

Procedure:
60 ml (60 mmol) of a 1N aqueous solution of sodium hydroxide are added, at ambient temperature, to 3.74 g (10 mmol) of methyl 2-amino-5-[1-bromo(imidazo[1,5-a]pyridin-3-yl)carbonyl]benzoate in 300 ml of methanol and 125 ml of water. The reaction medium is refluxed for 6 hours and then 140 ml of a 1N aqueous solution of hydrochloric acid are added. After concentration of the methanol under reduced pressure, the precipitate obtained is filtered off, washed with water, and then dried under reduced pressure at 40° C. for 18 hours. 3.53 g of a yellow solid are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19](O)=[O:20])=[C:14]([C:16](=[O:18])[NH2:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19]([NH:26][CH:23]4[CH2:25][CH2:24]4)=[O:20])=[C:14]([C:16]([NH2:17])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:22]=1
Reactant: NC(=O)c1nc2n(c1C(=O)O)C1CC(C1)c1ccc(Br)cc1-2
Reactant: NC1CC1
Product: NC(=O)c1nc2n(c1C(=O)NC1CC1)C1CC(C1)c1ccc(Br)cc1-2
Yield: 85 %

Procedure:
10-bromo-2-carbamoyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-3-carboxylic acid was reacted with cyclopropylamine similarly to as described in example 2 with non-critical modifications to afford 141 mg (85%) 10-bromo-N3-cyclopropyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide. 10-bromo-N3-cyclopropyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 29 mg (18%) of N3-cyclopropyl-10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2:5].[N+:6]([O-:9])([OH:8])=[O:7]>>[N+:6]([O-:9])([O-:8])=[O:7].[Ca+2:5].[N+:6]([O-:9])([O-:8])=[O:7]
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: O=[N+]([O-])[O-]

Procedure:
reacting calcium carbonate with nitric acid to form calcium nitrate;
Reaction SMILES: C([O:8][C:9](=[O:31])[CH:10]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:13][CH:12]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C>[C:27]([O:26][C:24]([NH:23][CH:10]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=1)[C:9]([OH:31])=[O:8])=[O:25])([CH3:29])([CH3:30])[CH3:28]
Reactant: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)c1ccc(/C=C/S(C)(=O)=O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(CCS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
A hydrogenation vessel containing tert-butoxycarbonylamino-[4-((E)-2-methanesulfonyl-vinyl)-phenyl]-acetic acid benzyl ester (1.1 g, 2.5 mmol) in methanol/ethyl acetate (3:1, 50 ml) was purged with nitrogen and 10% palladium on carbon (200 mg) added. The atmosphere above the organic solution was exchanged for hydrogen and the reaction mixture stirred vigorously for 3 hours at ambient temperature. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo to give tert-butoxycarbonylamino-[4-(2-methanesulfonyl-ethyl)-phenyl]-acetic acid (800 mg, 94%).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:34][S:35][CH2:36][C@H:37]([O:53][C:54](=[O:66])[NH:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:38][O:39][C:40](=[O:52])[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:13](=[O:33])[NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=O)C1C=CC=CC=1.C([O-])=O.[NH4+].CO.O>CO.[Pd]>[NH2:11][C@@H:12]([CH2:34][S:35][CH2:36][C@H:37]([O:53][C:54](=[O:66])[NH:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:38][O:39][C:40](=[O:52])[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:13](=[O:33])[NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Temperature: 40 °C

Procedure:
A solution of (15R,19R)-tert-butyl 15-(benzyloxycarbonylamino)-19-(decylcarbamoyloxy)-14,22-dioxo-4,7,10,21-tetraoxa-17-thia-13,23-diazatritriacontan-1-oate in MeOH (0.1 M) was stirred under nitrogen at room temperature. A small scoop (catalytic) of Pd/C was then added and stirred. A solution of ammonium formate (8 eq) in 9:1 MeOH/water was then added, the reaction vessel purged with nitrogen and heated to 40° C. for 4 hours. The reaction was then cooled to room temperature and diluted with EtOAc. The reaction mixture was filtered through celite then Na2SO4 and concentrated to afford the title compound as a light yellow oil. The concentrated material was used with no further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.[C:11](Cl)(=[O:14])[CH:12]=[CH2:13]>>[C:11]([NH:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1)(=[O:14])[CH:12]=[CH2:13]
Reactant: C=CC(=O)Cl
Reactant: Nc1cccc(B(O)O)c1
Product: C=CC(=O)Nc1cccc(B(O)O)c1

Procedure:
3-Acrylamido-phenylboronic acid (“3-APB”) was synthesised by reacting 3-amino phenylboronic acid with an excess of acryloyl chloride in an aqueous alkaline solution. The product was extracted in acetone and dried using a rotary evaporator. The structure of 3-APB was confirmed using NMR. The purity was about 90%, TLC showing very little contamination.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[CH:30]=[C:29](F)[N:28]=[CH:27][C:23]=4[N:24]=[CH:25][N:26]=3)=[CH:16][C:15]=2[CH3:32])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.CC1C=C(NC2C3C=C(N4CCOCC4)N=CC=3N=CN=2)C=CC=1OC1CCNCC1>>[C:1]([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[CH:30]=[C:29]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[N:28]=[CH:27][C:23]=4[N:24]=[CH:25][N:26]=3)=[CH:16][C:15]=2[CH3:32])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1Oc1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1OC1CCNCC1
Product: Cc1cc(Nc2ncnc3cnc(N4CCOCC4)cc23)ccc1Oc1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared from 4-[4-(6-Fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxy]-benzoic acid tert-butyl ester and morpholine by a procedure analogous to the synthesis of [3-Methyl-4-(piperidin-4-yloxy)-phenyl]-(6-morpholin-4-yl-pyrido[3,4-d]pyrimidin-4-yl)-amine. LRMS: 498.4 (MH+). 1H NMR (DMSO-d6, 400 MHz): δ 9.74 (s, 1H), δ 8.87 (s, 1H), δ 8.45 (s, 1H), δ 7.89-7.92 (m, 2H), δ 7.80-δ 7.83 (m, 2H), δ 7.55 (s, 1H), δ 7.12 (d, J=9.64, 1H), δ 6.95-6.98 (m, 2H), δ 3.80-3.83 (m, 4H), δ 3.58-δ 3.61 (m, 4H), δ 2.17 (s, 3H), δ 1.54 (s, 9H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([Cl:20])=[C:8]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:9]2=[N:10][C:11]=1[CH3:12])=O)C.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[Cl:20][C:7]1[C:6]([CH2:4][OH:3])=[C:11]([CH3:12])[N:10]=[C:9]2[S:13][C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:8]=12
Reactant: CCOC(=O)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Cc1nc2sc3c(c2c(Cl)c1CO)CCCC3
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of ethyl(4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)carboxylate (1.79 g; 5.78 mmol) in dry dichloromethane (18 mL) at −78° C. under nitrogen atmosphere was added a 1M solution of diisobutylaluminium hydride in dichloromethane (13.3 mL; 13.29 mmol). The resulting solution was stirred for 1.5 h and 1 h more at 0° C. The reaction mixture was quenched by adding 1N HCl carefully (17 mL) and the resulting mixture was vigorously stirred for 1 h. The phases were separated and the aqueous layer was extracted with dichloromethane. The organics were combined and washed with a Rochelle's salt solution and brine, dried over sodium sulphate, concentrated under reduced pressure to furnish 1.2 g (77%) of the title compound as an orange solid.
Reaction SMILES: [N:1]#[C:2]Br.[Cl:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[C:19]3[CH2:24][CH2:23][N:22](C)[CH2:21][CH2:20]3)[C:7]=2[CH:6]=1>C1C=CC=CC=1>[Cl:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[C:19]3[CH2:24][CH2:23][N:22]([C:2]#[N:1])[CH2:21][CH2:20]3)[C:7]=2[CH:6]=1
Reactant: CN1CCC(=C2c3ccccc3Oc3ccc(Cl)cc32)CC1
Reactant: N#CBr
Solvent: c1ccccc1
Product: N#CN1CCC(=C2c3ccccc3Oc3ccc(Cl)cc32)CC1
Temperature: 55 °C

Procedure:
A solution of cyanogen bromide (14.1 g., 0.133 mol) in benzene (200 ml) at 35° C. is treated with a solution of 4-(2-chloro-9-xanthenylidene)-1-methylpiperidine (31.2 g., 0.10 mol) in benzene (250 ml.) over 15 minutes. The solution is heated to 55° C. for four hours. The solvent is evaporated and the residue is recrystallized from ethanol to give 4-(2-chloro-9-xanthenylidene)-1-cyanopiperidine, m.p. 148°-150° C. A solution of the latter (27.2 g., 0.084 mol) in glacial acetic acid (450 ml.), water (250 ml.) and concentrated hydrochloric acid is refluxed for 18 hours, and the major portion of the solvent is evaporated. The residue is basified and extracted with ethylacetate. The extracts are washed with water and the solvent evaporated. The residue is triturated with ethanol, filtered and the filtrate is evaporated to leave 4-(2-chloro-9-xanthenylidene)piperidine. The free base is dissolved in acetonitrile and treated with one equivalent of methanesulfonic acid to yield 4-(2-chloro-9-xanthenylidene)piperidine methanesulfonate, m.p. 256°-260° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=2[CH3:17])[CH:6]=[CH:7][CH:8]=1.[CH2:18]([S:20][CH2:21][CH2:22]Cl)[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[CH2:18]([S:20][CH2:21][CH2:22][O:16][C:12]1[CH:11]=[C:10]([CH3:17])[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=2)=[C:14]([CH3:15])[CH:13]=1)[CH3:19]
Reactant: Cc1cc(O)cc(C)c1-c1cccc(CO)c1
Reactant: CCSCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSCCOc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Temperature: 95 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
To a solution of 3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol (1.83 g, 8.00 mmol) and 2-chloroethyl ethyl sulfide (1.07 mL, 12.0 mmol) in N,N-dimethylformamide (15 mL) were added potassium carbonate (1.33 g, 9.60 mmol) and potassium iodide (0.132 g, 0.800 mmol), and the mixture was stirred at 95° C. for 24 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50) to give the title compound (1.19 g, yield 47%) as a colorless oil.
Reaction SMILES: C([C:3]1(C(C2C=CC(OCC(OC)=O)=CC=2)=O)CC2C=CC=CC=2[O:4]1)C.[CH2:26]([C:28]1[O:29][C:30]2[CH:49]=[CH:48][CH:47]=[CH:46][C:31]=2[C:32]=1[C:33]([C:35]1[CH:45]=[CH:44][C:38]([O:39][CH2:40][C:41](N)=[O:42])=[CH:37][CH:36]=1)=[O:34])[CH3:27]>>[CH2:26]([C:28]1[O:29][C:30]2[CH:49]=[CH:48][CH:47]=[CH:46][C:31]=2[C:32]=1[C:33]([C:35]1[CH:45]=[CH:44][C:38]([O:39][CH2:40][C:41]([O:4][CH3:3])=[O:42])=[CH:37][CH:36]=1)=[O:34])[CH3:27]
Reactant: CCc1oc2ccccc2c1C(=O)c1ccc(OCC(N)=O)cc1
Reactant: CCC1(C(=O)c2ccc(OCC(=O)OC)cc2)Cc2ccccc2O1
Product: CCc1oc2ccccc2c1C(=O)c1ccc(OCC(=O)OC)cc1

Procedure:
Compound 11 was the intermediate of Example 7.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[N:9][CH:10]=2)[CH:7]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:17]#[C:18][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[N:9][CH:10]=3)[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccc2cnnn2c1
Reactant: C#Cc1ccccc1
Product: C(#Cc1ccc2cnnn2c1)c1ccccc1

Procedure:
The title compound, light brown solid, MS: m/e=220.3 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-[1,2,3]triazolo[1,5-a]pyridine (example 34, step 1) and phenylacetylene.