Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].C(=O)([O-])[O-].[Ca+2].[H][H]>O>[CH2:2]([OH:1])[C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: [H][H]
Reactant: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
24 g of Raney-nickel obtained by the method described above was added to 300 g of an aqueous solution containing 100 g of 6-deoxy L-mannose in a 1-L glass autoclave with an agitator and a thermometer, to which water was added to a final reaction volume of 600 g. So as to adjust the reaction mixture to pH 7, then, calcium carbonate was added. Reaction was progressed while the temperature was retained at 50° C.; the hydrogen pressure was retained at 12 kg/cm2 (gauge pressure); the agitation speed was retained at 700 rpm. The reaction mixture was analyzed by HPLC. Consequently, 6-deoxy L-mannose was decreased to 1% in the 8-hour reaction, to produce 6-deoxy L-mannitol.
Reaction SMILES: [C:1](=[O:53])([O:22][C:23]1[C:24]([CH3:52])=[C:25]2[C:30](=[C:31]([CH3:34])[C:32]=1[CH3:33])[O:29][C:28]([CH3:51])([CH2:35][CH2:36][CH2:37][CH:38]([CH3:50])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:49])[CH2:43][CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:27][CH2:26]2)[O:2][CH2:3][CH2:4][CH:5]([CH2:14][O:15]C1CCCCO1)[CH2:6][O:7]C1CCCCO1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[C:1](=[O:53])([O:22][C:23]1[C:24]([CH3:52])=[C:25]2[C:30](=[C:31]([CH3:34])[C:32]=1[CH3:33])[O:29][C:28]([CH3:51])([CH2:35][CH2:36][CH2:37][CH:38]([CH3:50])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:49])[CH2:43][CH2:44][CH2:45][CH:46]([CH3:47])[CH3:48])[CH2:27][CH2:26]2)[O:2][CH2:3][CH2:4][CH:5]([CH2:14][OH:15])[CH2:6][OH:7]
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)OCCC(COC1CCCCO1)COC1CCCCO1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1OC(=O)OCCC(CO)CO)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
27.5 g (0.037 mol) of the 4-(2-tetrahydro-pyranyloxy)-3-(2-tetrahydropyranyloxymethyl)butyl 2,5,7,8-tetramethyl-2-(4',8', 12'-trimethyltridecyl)-6-chromanyl carbonate prepared in the above step was dissolved in 300 ml of methanol. To the obtained solution was added 5 g of p-toluenesulfonic acid followed by stirring at room temperature for 1 hour. 1 l of water was added to the reaction mixture and the oily matter thus separated out was extracted with ether. The extract was washed with water and dried. After distilling off the solvent, the obtained oily residue was purified by column chromatography (silica gel, hexane : ethyl acetate=3:1). Thus 16.5 g of the title compound was obtained as a colorless viscous liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[CH2:8][CH2:7][CH2:6]2.CN(C=O)C.[Cl-:20]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([Cl:20])=[O:14])[CH2:8][CH2:7][CH2:6]2
Reactant: [Cl-]
Reactant: COc1cc2c(cc1C(=O)O)CCC2
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C(=O)Cl)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-methoxyindan-6-carboxylic acid (3.84 g), DMF (0.1 ml) and tetrahydrofuran (50 ml) was added oxyalyl chloride (2.1 ml) dropwise. The mixture was stirred at room temperature for 1 hour, at the end of which time the solvent was distilled off to give 5-methoxyindan-6-carboxylic acid chloride. This chloride was dissolved in dichloromethane (50 ml) and after addition of 2,6-di-tert-butylphenol (4.12 g), tin tetrachloride (2.6 ml) was added dropwise with ice-cooling. The mixture was stirred under ice-cooling for 30 minutes and, then, poured in diluted hydrochloric acid. The organic layer was washed with water and dried (MgSO4) and the solvent was distilled off. To the residue was added ethanol-hexane to give crystals of 5-(3,5-di-tert-butyl-4-hyroxybenzoyl)-6-methoxyindan (4.23 g, 55.7%). Recrystallization from ethanol gave colorless prisms, m.p. 154°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.Cl.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:26]3[CH2:25][CH2:24][N:23]([C:19]4[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH3:15])[CH:18]=4)[CH2:28][CH2:27]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: COc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: OCCO
Solvent: CCN(CC)CC
Product: COc1cccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c1
Yield: 72.7 %

Procedure:
Following the general procedure of Example 11 and making noncritical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.409 g), 1-(3-methoxyphenyl)piperazine dihydrochloride (Aldrich; 0.450 g), triethylamine (Aldrich; 0.686 g), and ethylene glycol (2 mL) give 0.440 g of the title compound after chromatography (silica gel, methanol/dichloromethane, 4/96) and crystallization from dichloromethane/ethyl ether/hexane; mp 132-133.5° C.; MS m/z 356; IR (mineral oil) 805, 2817, 1198, 1171, 1580, 1502 cm-1. 1H NMR (CDCl3) δ2.74, 3.24, 3.78, 6.41, 6.46, 6.55, 7.11-7.19, 7.52, 7.56, 8.14.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:2]1.CCN(C(C)C)C(C)C.[Br:19][C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C@H:33]([NH:37][C:38]([C:40]3[S:41][C:42]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:43][CH:44]=3)=[O:39])[C:34](O)=[O:35])=[CH:28][CH:27]=2)=[N:24][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:19][C:20]1[CH:25]=[N:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([CH2:32][C@H:33]([NH:37][C:38]([C:40]3[S:41][C:42]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:43][CH:44]=3)=[O:39])[C:34]([N:1]3[CH2:5][CH2:4][C@H:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:2]3)=[O:35])=[CH:30][CH:31]=2)=[N:22][CH:21]=1
Reactant: CC(C)(C)c1ccc(C(=O)N[C@@H](Cc2ccc(-c3ncc(Br)cn3)cc2)C(=O)O)s1
Reactant: COC(=O)[C@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CCN(C(=O)[C@H](Cc2ccc(-c3ncc(Br)cn3)cc2)NC(=O)c2ccc(C(C)(C)C)s2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a stirring solution of methyl (S)-pyrrolidine-3-carboxylate (357.0 mg, 2.16 mmol) in DMF (10 mL) were added DIEA (465.26 mg, 3.60 mmol) and (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoic acid (700.0 mg, 1.44 mmol). The solution was cooled to 0° C. at ice bath and then HATU (677.55 mg, 2.88 mmol) in 2 mL DMF solution was slowly added. The reaction was stirred 1 hour at 0° C. and then warmed to RT with stirring for 2 hours. The reaction solution was extracted with DCM (3×20 mL) and aqueous NaHCO3 (3×10 mL). The combined organics were dried over MgSO4 and evaporated. The final compound was purified by column chromatography (40% DCM in hexane) to afford 501.0 mg (58%) of methyl (S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)pyrrolidine-3-carboxylate INT-35 as a powder. LCMS-ESI (m/z calculated for C28H31BrN4O4S: 598.1. found 599.3 [M+H]+, tR=3.553 min. (Method 16). 1H NMR (400 MHz, DMSO) δ 9.05 (d, J=1.1 Hz, 2H), 8.77 (dd, J=11.5, 8.3 Hz, 1H), 8.25 (d, J=7.7 Hz, 2H), 7.72 (d, J=3.5 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 6.92 (d, J=3.8 Hz, 1H), 4.98-4.73 (m, 1H), 3.88 (dd, J=10.3, 8.0 Hz, 1H), 3.71 (dd, J=15.5, 7.5 Hz, 1H), 3.50 (ddd, J=18.3, 12.2, 5.4 Hz, 2H), 3.38 (dd, J=17.3, 7.6 Hz, 1H), 3.23 (ddd, J=28.0, 15.0, 8.7 Hz, 1H), 3.18-2.85 (m, 3H), 2.17-1.96 (m, 2H), 1.87 (td, J=15.2, 7.4 Hz, 1H), 1.32 (s, 9H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1.[NH:20]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21]1.C(=O)([O-])O.[Na+]>C(O)CCC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16]([N:20]3[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21]3)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1
Reactant: O[C@H]1CCNC1
Reactant: Clc1ccc2ncc(-c3cc4ccccc4o3)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: O[C@H]1CCN(c2ccc3ncc(-c4cc5ccccc5o4)n3n2)C1

Procedure:
150 mg (0.56 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine, 116.3 mg (1.34 mmol) (3S)-pyrrolidin-3-ol and 112.1 mg (1.34 mmol) sodium hydrogencarbonate in 4.0 mL butan-1-ol were stirred 72 h at 150° C. The solvent was removed. The residue was purified by HPLC to yield 22 mg (12%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>CC(C)=O>[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][O:14][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1ccccc1CBr
Reactant: Oc1cc(Nc2nccs2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1ccccc1COc1cc(Nc2nccs2)ccc1Cl
Yield: 58 %

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture of 2-chloro-5-(thiazol-2-ylamino)phenol (50 mg, 0.22 mmol) and Cs2CO3 (72 mg, 0.22 mmol) in acetone (4.4 mL) was treated with 2-methylbenzyl bromide (41 mg, 0.22 mmol) at RT. Reaction control by TLC showed full conversion after 3 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 4/1) in 58% yield (42 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]=O)[CH2:30][CH2:29]1)=[O:27])C1C=CC=CC=1.[C:37]([O:41][C:42](=[O:49])[C@H:43]([CH2:45][CH:46]([CH3:48])[CH3:47])[NH2:44])([CH3:40])([CH3:39])[CH3:38]>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][NH:44][C@H:43]([C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:49])[CH2:45][CH:46]([CH3:47])[CH3:48])[CH2:30][CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2CCC(CC=O)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Product: CC(C)C[C@H](NCCC1CCN(C(=O)c2cc(C(C)C)c(O)cc2O)CC1)C(=O)OC(C)(C)C

Procedure:
Prepared from Intermediate D and L-leucine tert-butyl ester. 1H NMR (300 MHz, d3-MeOD) 6.95 (1H, s), 6.33 (1H, s), 4.17 (2H, m), 3.33 (1H, m), 3.28 (1H, m), 2.95 (2H, t, J=12.6 Hz), 2.65 (2H, m), 1.74 (4H, m), 1.57 (11H, m), 1.44 (4H, m), 1.20 (6H, d, J=9.0 Hz), 0.97 (6H, m). LC/MS: purity 96%, m/z 477 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:15]>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1c(Cl)cc(Cl)cc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Yield: 93 %

Procedure:
A solution of 2,4,6-trichlorobenzoic acid (1.0 g, 4.0 mmol) in SOCl2 (5 mL) was heated to reflux for 30 min under nitrogen atmosphere. The reaction was concentrated under reduced pressure to give 2,4,6-trichlorobenzoyl chloride (900 mg, 93% yield), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N:27]=[C:26]2[NH:34][CH:35]2[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][N:43]=[C:44]=[S:45])[CH2:37][CH2:36]2)=[CH:20][CH:19]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:44]([NH:43][CH2:42][CH2:41][N:38]2[CH2:39][CH2:40][CH:35]([NH:34][C:26]3[N:25]([CH2:24][C:21]4[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=3)[CH2:36][CH2:37]2)=[S:45])=[CH:6][CH:7]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Reactant: Nc1ccccc1NCc1ccc(F)cc1
Solvent: C1CCOC1
Product: Fc1ccc(CNc2ccccc2NC(=S)NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Yield: 100 %

Procedure:
A mixture of 2.1 parts of N-(4-fluorophenylmethyl)-1,2-benzenediamine, 4 parts of 1-(4-fluorophenylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine and 90 parts of tetrahydrofuran is stirred and refluxed for 2 hours. The reaction mixture is evaporated, yielding 6 parts (100%) of N-{2-[(4-fluorophenylmethyl)amino]phenyl}-N'-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}-ethyl]thiourea as a residue.
Reaction SMILES: [Cl:1][Si:2]([CH3:10])([CH3:9])[CH:3]=[CH:4][Si:5]([Cl:8])([CH3:7])[CH3:6].ClC([SiH2][CH:15]=[C:16]([SiH2]C(Cl)Cl)CC)Cl>>[Cl:1][Si:2]([CH3:10])([CH3:9])[CH2:3][CH:4]([Si:5]([Cl:8])([CH3:7])[CH3:6])[CH2:15][CH3:16]
Reactant: CCC(=C[SiH2]C(Cl)Cl)[SiH2]C(Cl)Cl
Reactant: C[Si](C)(Cl)C=C[Si](C)(C)Cl
Product: CCC(C[Si](C)(C)Cl)[Si](C)(C)Cl

Procedure:
Example 1 was repeated with the modification that, instead of 300.0 g (1.41 mol) of 1,2-bis(chlorodimethylsilyl)ethene, 300.0 g (1.24 mol) of 1,2-bis(dichloromethylsilyl)but-1-ene were used. The results are summarized in Table 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](B(O)O)=[CH:10][C:11]3[O:15][CH2:14][O:13][C:12]=3[CH:16]=2)=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:10][C:11]3[O:15][CH2:14][O:13][C:12]=3[CH:16]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: OB(O)c1cc2c(cc1-c1ccc(F)cc1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1ccc(-c2cc3c(cc2-c2ccc(F)cc2)OCO3)cc1
Yield: 75.8 %

Procedure:
Under nitrogen, 500 mg of Pd(PPh3)4 was added to a stirred solution of 1.55 g (6.0 mmol) of [6-(4-fluorophenyl)-1,3-benzodioxol-5-yl]boronic acid (Step 2) and 1.09 g (4.62 mmol) of 4-bromobenzenesulfonamide (Lancaster) in 30 mL of toluene, 20 mL of ethanol, and 15 mL of 2M Na2CO3. After vigorous stirring at reflux for 6 hours, the solvent was removed in vacuo and the residue dissolved in ethyl acetate. The resulting solution was washed with water and dried over Na2SO4. Purification by silica gel chromatography (MPLC) with ethyl acetate/hexane (3:7) gave 1.3 g (76%) of 4-[6-(4-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide as a colorless solid: mp 191.0-192.5° C.; NMR (CDCl3) δ 4.80 (s, 2H), 6.06 (s, 2H), 6.83-6.92 (m, 4H), 6.97-7.06 (m, 2H), 7.20 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H). MS (FAB): m/e 372 (M+H). Anal. Calc'd for C19H14FNO4S: C, 61.45; H, 3.80; N, 3.77. Found: C, 61.48; H, 3.92; N, 3.68.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:7])([CH3:4])[CH3:3].[Si](C=[N+]=[N-])(C)(C)[CH3:19]>C(Cl)Cl.CO>[NH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C:15]([O:17][CH3:19])=[O:16]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCCN)C(=O)O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H](CCCCN)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A solution of N-α-Boc-D-lysine 12 (1.00 g, 4.06 mmol) in CH2Cl2 (20 mL) and MeOH (5.0 mL) was charged with TMS-diazomethane [(CH3)3SiCHN2 0.6 M solution in hexane, 13.5 mL, 8.12 mmol] at 0° C. and stirred at the same temperature for 1 h and at room temperature for another 1 h. The solvent was removed under reduced pressure to afford crude product 14 (1.04 g, crude) as a yellow oil, which was directly used for the next step without further purification: 1H NMR (400 MHz, CD3OD) δ 4.12-4.05 (m, 1H), 3.70 (s, 3H), 2.62 (t, J=7.0 Hz, 2H), 1.82-1.70 (m, 1H), 1.69-1.58 (m, 1H), 1.54-1.32 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[CH2:23][N:24]=[C:25]=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.Cl.CNC>ClCCl.O>[CH3:23][N:24]([CH3:25])[C:19](=[O:21])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(CC(=O)O)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution is prepared of 1.2 g (4.06 mmol) of 4-[2-(Boc-amino)ethoxy]benzeneacetic acid in 4 ml of dichloromethane and then 932 mg (4.87 mmol) of EDCI and 55 mg (0.406 mmol) of HOAT are added. After 10 minutes under agitation at ambient temperature, 400 mg (4.87 mmol) of dimethylamine hydrochloride are added. The reaction medium is then agitated at ambient temperature for 24 hours. The medium is then treated by the addition of 20 ml of water and then extracted 3 times with 50 ml of dichloromethane. The organic phases are then regrouped and washed 3 times with 50 ml of water, then dried on magnesium sulfate, and concentrated under reduced pressure. The raw product obtained is then purified by silica gel chromatography eluting with the help of a dichloromethane/ethanol mixture (95/5; v/v). In this way the expected product is obtained in the form of a colorless oil (yield=46%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4C(OC(C)(C)C)=O)[CH2:12][C:13]([O:15]C)=[O:14])=[N:8][C:7]=2[CH:36]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CO.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH2:12][C:13]([OH:15])=[O:14])=[N:8][C:7]=2[CH:36]=1)#[N:2]
Reactant: COC(=O)CC(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1C(CC(=O)O)c1nc2cc(C#N)ccc2o1
Temperature: 65 °C

Procedure:
(±)-tert-Butyl 4-(1-(5-cyanobenzo[d]oxazol-2-yl)-3-methoxy-3-oxopropyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 148-A) (0.3 g, 0.613 mmol) was dissolved in MeOH (6 ml). cesium carbonate (0.998 g, 3.06 mmol) was added and the reaction was heated at 65° C. for 2.5 hours. The reaction was then cooled to room temperature and treated with 1 N HCl until pH=˜3. The mixture was then diluted with DCM and passed through a phase separator, concentrated and purified via preparative HPLC (HC-B) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.00 (br. s., 1H) 8.34 (t, J=1.14 Hz, 1H) 7.58-7.92 (m, 2H) 7.22 (t, J=2.78 Hz, 1H) 6.77 (s, 1H) 6.22 (dd, J=3.03, 1.89 Hz, 1H) 5.39 (dd, J=9.85, 4.67 Hz, 1H) 3.72 (s, 3H) 3.57 (dd, J=16.67, 9.98 Hz, 1H) 2.74 (dd, J=16.67, 4.67 Hz, 1H) 2.44 (d, J=0.63 Hz, 3H). HRMS calcd. for C21H17N3O4 (M+H)+ 376.1297. found 376.1290.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([N:20]1[C:25](=[O:26])[C:24]2=[C:27]([Cl:30])[CH:28]=[CH:29][N:23]2[N:22]=[C:21]1[CH:31](Cl)[CH:32]1[CH2:34][CH2:33]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN1C(=O)CCC1>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:31]([C:21]1[N:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:25](=[O:26])[C:24]2=[C:27]([Cl:30])[CH:28]=[CH:29][N:23]2[N:22]=1)[CH:32]1[CH2:33][CH2:34]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=c1c2c(Cl)ccn2nc(C(Cl)C2CC2)n1Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NCCCNC(c1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1)C1CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 80.9 %

Procedure:
(3-Amino-propyl)-carbamic acid tert-butyl ester (Fluka, 0.527 mL, 3.02 mmol) was added to a solution of 3-benzyl-5-chloro-2-(chloro-cyclopropyl-methyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (0.35 g, 1.01 mmol) in NMP (3.3 mL) at room temperature. The reaction mixture was degassed with N2 and then stirred at 100° C. for 12 h. The reaction mixture was cooled to room temperature and the crude product was purified by loading directly onto a reverse phase C-18 HPLC with a 30 min gradient eluting with 45–90% aqueous methanol with 0.1% TFA to afford the title compound (0.397 g, 81%) as a solid: 1H NMR (DMF-d7) 7.74 (m, 1H), 7.35–7.49 (m, 5H), 6.85 (m, 2H), 5.85 (m, 1H), 5.45 (m, 1H), 3.15–3.25 (m, 3H), 2.70–2.85 (m, 2H), 2.55 (br m, 1H), 1.55–165 (m, 2H), 1.47 (s, 9H), 1.40 (br m, 1H), 0.65–0.75 (m, 1H), 0.41–0.46 (m, 2H), 0.15 (br m, 1H); MS (ESI+) 486 (M++H); HRMS (ESI+) calculated: 486.2272 (M++H). found: 486.2256 (M++H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:27]([O:29]CC)=[O:28])=[C:21]([C:23]([NH:25][CH3:26])=[O:24])[N:22]=2)[CH2:14][C@@H:13]1[O:32][CH3:33])=[O:10].[OH-].[Ba+2].[OH-].O.Cl>CO>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:27]([OH:29])=[O:28])=[C:21]([C:23]([NH:25][CH3:26])=[O:24])[N:22]=2)[CH2:14][C@@H:13]1[O:32][CH3:33])=[O:10]
Reactant: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)nc1C(=O)NC
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNC(=O)c1nc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)sc1C(=O)O

Procedure:
To a suspension/solution of ethyl 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-[(methylamino)carbonyl]-1,3-thiazole-5-carboxylate (0.078 g, 0.15 mmol, Example 218) in methanol (2 mL) was added barium hydroxide (0.052 g, 0.30 mmol) and water (0.5 mL). After stirring several hours the reaction was complete. The reaction was acidified with 1N HCl and then concentrated to remove methanol. The residue was extracted with EtOAc (×3), dried with MgSO4 and concentrated to a white solid (0.059 g). MS (ES) M+H+: 490 for C18H21Cl2N5O5S; NMR: 1.76 (s, 2 H) 2.18 (s, 3 H) 2.86 (s, 3 H) 3.38 (s, 3 H) 3.56 (s, 2 H) 4.02 (s, 1 H) 4.27 (s, 2 H) 4.40 (s, 1 H) 7.15 (s, 1 H) 9.38 (s, 1 H) 12.15 (s, 1 H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:24]1[C:25]2[C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])=[CH:34][S:33][C:26]=2[N:27]=[C:28]([CH:30]2[CH2:32][CH2:31]2)[N:29]=1>C(O)C>[CH:30]1([C:28]2[N:29]=[C:24]([N:13]3[CH2:14][CH2:15][CH:10]([CH2:9][O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:11][CH2:12]3)[C:25]3[C:35]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[O:42][CH3:43])=[CH:34][S:33][C:26]=3[N:27]=2)[CH2:32][CH2:31]1
Reactant: C1CCN(CCOCC2CCNCC2)C1
Reactant: COc1ccccc1-c1csc2nc(C3CC3)nc(Cl)c12
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1csc2nc(C3CC3)nc(N3CCC(COCCN4CCCC4)CC3)c12
Yield: 19 %

Procedure:
4-(2-Pyrrolidin-1-ylethoxymethyl)piperidine (0.10 g, 0.47 mmol), triethylamine (0.089 mL, 0.63 mmol) and 4-chloro-2-cyclopropyl-5-(2-methoxyphenyl)thieno[2,3-d]pyrimidine (0.10 g, 0.32 mmol) were combined and heated to 50° C. in ethanol (10 mL) overnight. The solvent was removed at reduced pressure. The residue was taken up in DCM (20 mL), washed with water (20 mL) and the organic dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by flash chromatography, eluting with a gradient of DCM to 90/10/1 DCM/MeOH/NH4OH to afford 2-cyclopropyl-5-(2-methoxyphenyl)-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidine (0.03 g). LCMS: purity 100%, RT=3.62 min, M+1=493.1