Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl.O>CN(C=O)C>[Br:1][C:2]1[CH:16]=[N:15][C:5]2[N:6]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: N#Cc1cc2c(cn1)[nH]c1ncc(Br)cc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a suspension of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (300 mg, 1.1 mmol) in DMF (2.5 mL), under an inert atmosphere, was added sodium hydride (65 mg, 1.3 mmol) and the reaction mixture was allowed to stir at ambient temperature for 30 minutes. The reaction mixture was cooled to 0° C. and 2-(trimethylsilyl)ethoxymethyl chloride (0.25 mL, 1.3 mmol) was added dropwise and then the resultant suspension was allowed to warm to room temperature. Water (0.5 mL) was added to the resultant suspension to quench the reaction, the solvent was removed in vacuo and the resultant residue was purified by flash chromatography (silica, 12 g column, ISCO, 0-15% ethyl acetate in cyclohexane) to afford the title compound as an off-white crystalline solid (266 mg, 62%). 1H NMR (CDCl3, 400 MHz): 9.18 (d, J=1.2 Hz, 1H), 8.74 (d, J=2.3 Hz, 1H), 8.58 (d, J=2.3 Hz, 1H), 8.34 (d, J=1.2 Hz, 1H), 5.98 (s, 1H), 3.56-3.60 (m, 2H), 0.94-0.98 (m, 2H), 0.08 (s, 9H). LCMS (Method B): RT=4.55 min, M+H+=(403, 405).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]2[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O[C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]2[C:21]2[CH:22]=[CH:23][C:24]([O:27][C@H:29]([CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][CH:26]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 25.2 %

Procedure:
To a solution of 4-[1-(4-heptyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenol (640 mg, 1.76 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (513 mg, 2.64 mmol) and triphenylphosphine (692 mg, 2.64 mmol) in toluene (2 ml) was added 1,1′-(azodicarbonyl)dipiperidine (666 mg, 2.64 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 240 mg (yield: 25.2%)
Reaction SMILES: C[Li].[OH:3][C:4]1[C:9]2[C:10](=[O:24])[C:11]3[C:16]([C:17]4([CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.Cl.[C:26](=O)([O-])[O-].[Na+].[Na+]>CCOCC.O>[OH:3][C:4]1[C:9]2[C:10]([OH:24])([CH3:26])[C:11]3[C:16]([C:17]4([CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]4)[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: CN1CCC2(CC1)c1ccccc1C(=O)c1c(O)cccc12
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Li]C
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CN1CCC2(CC1)c1ccccc1C(C)(O)c1c(O)cccc12
Reaction time: 1 h

Procedure:
Methyl lithium in ether (5 ml., 1.5M) is added dropwise with stirring under nitrogen to 4-hydroxy-1'-methyl-10-oxo-9,10-dihydroanthracene-9-spiro-4'-piperidine (0.7 g.) in dry ether (25 ml.) and the mixture is stirred for 1 hour then diluted with water, acidified (2N hydrochloric acid), basified with sodium carbonate, and extracted with ethyl acetate. The ethyl acetate extract is washed with water and with brine, dried (MgSO4), evaporated, and the residue is recrystallised from ethanol to give 4,10-dihydroxy-1',10-dimethyl-9,10-dihydroanthracene-9-spiro-4'-piperidine, m.p. 151°-154°C.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH:2]=[CH:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+].[S:11](=[O:14])([OH:13])[O-:12].[Na+].S(=O)(O)[O-]>>[S:11]([CH:3]([CH2:4][CH2:5][CH3:6])[CH2:2][C:1]([OH:8])=[O:7])([OH:14])(=[O:13])=[O:12]
Reactant: CCCC=CC(=O)O
Reactant: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Product: CCCC(CC(=O)O)S(=O)(=O)O

Procedure:
114 g. of 2-hexenoic acid is neutralized with aqueous sodium hydroxide and reacted with 204 g. of a 50% wt. aqueous solution of sodium bisulfite at 25° C. Complete addition of bisulfite to the double bond requires several hours. The product is concentrated to approximately 50% wt. solids and then treated with a strong acid ion exchange resin to obtain an aqueous solution of 3-sulfohexanoic acid. This is dried by vacuum stripping and converted into 3-propyl-1,2-oxathiolane-5-one-2,2-dioixde with refluxing thionyl chloride at 80° C. for 3 hours. Equivalent weight is 93.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][OH:20])=[CH:16][CH:15]=1>ClCCl>[CH3:8][S:9]([O:20][CH2:19][CH2:18][C:17]1[CH:21]=[CH:22][C:14]([O:13][S:9]([CH3:8])(=[O:11])=[O:10])=[CH:15][CH:16]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(OS(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 88080.2 %

Procedure:
27.3 g (0.27 mmole) triethylamine and a solution of 27.2 g (0.239 g mmole) methane sulfonyl chloride in dichloromethane were added to a solution of 15 g (0.108 mmole) p-hydroxyphenethyl alcohol in dichloromethane at 0° C. The reaction was allowed to reach room temperature, then stirred at room temperature and followed by TLC. The reaction mixture was filtered and the filtrate was washed with water. The solution was dried with sodium sulfate and then evaporated in vacuo to give 28 g (yield 88%) of 4-(methylsulfonyloxy)phenethyl methanesulfonate.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[C:18](C(OCC)=O)=[C:17]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[C:16]([N+:33]([O-:35])=[O:34])=[C:15]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[F:44])[N:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:38]1[CH:39]=[C:40]([F:43])[CH:41]=[CH:42][C:37]=1[CH2:36][C:15]1[C:16]([N+:33]([O-:35])=[O:34])=[C:17]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:31][CH:32]=2)[C:18]2[C:6](=[O:5])[N:8]3[C@@H:9]([CH2:10][CH2:11][CH2:12]3)[C:13]=2[N:14]=1
Reactant: CCOC(=O)c1c([C@@H]2CCCN2C(=O)OC(C)(C)C)nc(Cc2ccc(F)cc2F)c([N+](=O)[O-])c1-c1ccc(C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2c3c(nc(Cc4ccc(F)cc4F)c2[N+](=O)[O-])[C@@H]2CCCN2C3=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To the flask containing crude 4-[2-[(2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl]-6-(2,4-difluorobenzyl)-3-(ethoxycarbonyl)-5-nitro-4-pyridinyl]benzoic acid (D, 22.2 g, 36.3 mmol), 200 ml premixed trifloroacetic acid and dichloromethane (10 ml/4.2 ml ratio) was added. The resulting mixture was stirred at room temperature for 20 minutes. The solvents were removed in vacuo. The resulting residue was dissolved in 150 ml mixture of triethyl amine and dichloromethane (10 ml/20 ml) and was stirred at room temperature for 2 hours.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.C(=O)[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15]>C(O)(=O)C>[CH:1]1[CH:2]=[CH:3][C:4]([CH:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:6]=1.[CH:17]1[C:18]([CH:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:19][CH:13]=[C:14]([OH:15])[CH:16]=1
Reactant: N[C@H](C(=O)O)c1ccccc1
Reactant: O=Cc1ccccc1O
Solvent: CC(=O)O
Product: NC(C(=O)O)c1ccc(O)cc1
Product: NC(C(=O)O)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
6 g of L-phenylglycine or L-p-hydroxyphenylglycine were suspended in a mixture of 20 ml of 95% acetic acid and 0.2 ml (0.05 mole per mole of the L-amino acid used) of salicylaldehyde. The suspension was stirred at 100° C. for 2 hours. After the reaction, the mixture was cooled to room temperature, and the crystalline precipitates were collected by filtration and then washed with methanol. DL-phenylglycine or DL-p-hydroxyphenylglycine was thereby obtained. The results are shown in Table 17.
Reaction SMILES: [NH2:1][C:2]1C=C(O)[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[O:18]1[CH2:23][CH2:22]OCC1>>[CH2:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:22][C:23]=1[OH:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCBr
Reactant: C1COCCO1
Reactant: Nc1cccc(O)c1
Product: CCCCCCCCNc1ccccc1O

Procedure:
A solution of 5.45 g of 3-aminophenol and 11.6 g of 1-bromooctane in 250 ml of dioxane is stirred at 100° C. for 80 hours, the solvent is then evaporated, and the residue is then taken up in toluene/ethyl acetate (10:1) and chromatographed on silica gel, giving N-octylaminophenol as beige crystals, melting point 75° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:27])[C:20]([OH:26])=[CH:21][CH:22]=3)[C:17]2=[O:28])=[C:13]([CH3:29])[CH:12]=[C:11]([CH3:30])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Br[C:34](P(=O)(OCC)OCC)([F:36])[F:35]>CC#N.O.CCOC(C)=O.O>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:27])[C:20]([O:26][CH:34]([F:36])[F:35])=[CH:21][CH:22]=3)[C:17]2=[O:28])=[C:13]([CH3:29])[CH:12]=[C:11]([CH3:30])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Reactant: Cc1cc(C)c(CN2CCc3ccc(O)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Cc1cc(C)c(CN2CCc3ccc(OC(F)F)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
To a solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (1h, 0.1 g, 0.237 mmol) and KOH (0.265 g, 4.74 mmol) in CH3CN/H2O (10 mL/1 mL) was added diethyl [bromo(difluoro)methyl]phosphonate (0.126 g, 0.474 mmol) at −78° C. under N2 atmosphere. The resulting mixture was allowed to warm to room temperature and stirred for 30 minutes. The mixture was diluted with EtOAc (20 mL) and H2O (5 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×10 mL). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep. TLC (petroleum ether/EtOAc, 4:1) to obtain 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-(difluoromethoxy)-3,4-dihydroisoquinolin-1(2H)-one (1i, 0.08 g, 72%) as a yellow oil.
Reaction SMILES: CO.[OH-].[Ca+2:4].[OH-].[C:6]([OH:25])(=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[C:26](=[O:28])=[O:27]>O.C(O)CCCCCCC>[C:6]([O-:25])(=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[Ca+2:4].[C:6]([O-:25])(=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[C:26](=[O:24])([O-:28])[O-:27]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: O=C=O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CCCCCCCCO
Solvent: CO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Product: O=C([O-])[O-]
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 40 g of methanol, 30 g of octanol and 280 g of process oil (PUREXX12 : Esso Petroleum) was added 111 g of calcium hydroxide gradually to disperse it, 86 g of oleic acid was added, the mixture was stirred for 30 minutes, and carbon dioxide (20 L/hour) was blown thereinto at 50° C. for 6 hours to progress reaction. The mixture was gradually warmed to 160° C. to continue reaction while the formed water and the alcohol were distilled off, and then filtered to give a brown solution of an overbased calcium oleate-carbonate complex (Ca content=6.9% by weight; metal ratio=5.2) (this product is designated S-1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15]Cl)[CH:6]=[C:5]2[CH:19]=[O:20].[C:21]([O-:24])(=[O:23])[CH3:22].[Na+].[I-].[Na+]>CS(C)=O.O>[C:21]([O:24][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][N:7]1[CH:6]=[C:5]([CH:19]=[O:20])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[C:8]1=[O:12])(=[O:23])[CH3:22]
Reactant: CC(C)(CCl)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)OCC(C)(C)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Temperature: 100 °C
Reaction time: 10 h
Yield: 52.1 %

Procedure:
A solution of 6-bromo-2-(3-chloro-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinoline-4-carbaldehyde (Example 1d, 0.45 g) in dimethylsulfoxide (10 mL) was treated with sodium acetate (0.343 g) under nitrogen. The resulting mixture was stirred at 100° C. for 10 h. Sodium iodide (1 eq) was added and the reaction heated at 120° C. for 30 h. The reaction mixture was diluted with water (250 mL) and the solid filtered off and dried to afford the subtitle compound (0.25 g) as a solid.
Reaction SMILES: [OH:1]C1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.S(Cl)(Cl)(=O)=O.[N-:23]=[N+:24]=[N-:25].[N-:26]=[N+:27]=[N-:28].[C:29]1(=O)[C:38]2[C:33]([C:34](=[O:39])[CH:35]=[CH:36][CH:37]=2)=[CH:32][CH:31]=[CH:30]1.C(N(CC)CC)C>O1CCOCC1>[N-:23]=[N+:24]=[N-:25].[N-:26]=[N+:27]=[N-:28].[C:37]1(=[O:1])[C:38]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34](=[O:39])[CH:35]=[CH:36]1
Reactant: O=C1C=CC=C2C(=O)C=CC=C12
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [N-]=[N+]=[N-]
Solvent: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1C=CC(=O)c2ccccc21
Temperature: 40 °C

Procedure:
11.4 g (0.05 mol) of bisphenol A (result of calculation of dipole moment based on MOPAC-97=2.1 debye) and 34.9 g (0.13 mol) of 5-naphthoquinone diazide sulphonyl chloride were dissolved in 400 g of 1,4-dioxane under a current of dry nitrogen, and then warmed to 40° C. To this there was added, dropwise, 13.1 g (0.13 mol) of triethylamine mixed with 40 g of 1,4-dioxane, and then naphthoquinone diazide compound (4) was obtained in the same way as in Synthesis Example 1. (As an average, 1.3 of the Q groups=5-naphthoquinone diazide sulphonyl groups and 0.7=hydrogen.)
Reaction SMILES: [C:1]([NH:16][CH:17](O)[CH2:18][CH3:19])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1.N1[C-]=NN=N1.C([NH2+]C(C)C)(C)C.[CH:33]([N:36]([CH:50]([CH3:52])[CH3:51])[P:37](N(C(C)C)C(C)C)[O:38][CH2:39][CH2:40][C:41]#[N:42])([CH3:35])[CH3:34].C(=O)(O)[O-:54].[Na+]>CN(C=O)C>[CH:33]([N:36]([CH:50]([CH3:52])[CH3:51])[P:37]([O:38][CH2:39][CH2:40][C:41]#[N:42])[O:54][CH2:19][CH2:18][CH2:17][NH:16][C:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1)([CH3:35])[CH3:34]
Reactant: O=C([O-])O
Reactant: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Reactant: CCC(O)NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CC(C)[NH2+]C(C)C
Agent: [Na+]
Agent: [c-]1nnn[nH]1
Solvent: CN(C)C=O
Product: CC(C)N(C(C)C)P(OCCC#N)OCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 150 mg of N-biotinylaminopropanol (2b) in 5 ml of dry DMF was added 65 mg of diisopropylammonium tetrazolide and 0.300 ml of 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorodiamidite. The resulting solution was stirred at room temperature for 1.0 hr and then poured onto 50 ml of 5% aqueous sodium bicarbonate. The mixture was extracted with two 50 ml portions of methylene chloride, and the combined extracts were washed with 5% sodium bicarbonate and brine, dried over sodium sulfate, and evaporated to afford the crude product as a thick oil. This was dissolved in 2 ml of dry methylene chloride affording a solution that was added dropwise to 30 ml of rapidly stirring petroleum ether. The colorless precipitate which formed was collected by suction filtration under argon, affording after drying at room temperature under vacuum 151 mg (60%) of a colorless solid.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:6]=1/[CH:7]=[N:8]/[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([CH3:3])[CH3:2].C(N(CC)CC)C>ClCCl.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[CH:1]([S:4][C:5]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:6]=1[CH:7]1[CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:9][NH:8]1)([CH3:3])[CH3:2]
Reactant: COC(=O)CCC/N=C/c1cc([N+](=O)[O-])ccc1SC(C)C
Agent: [Ti+4]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCNC1c1cc([N+](=O)[O-])ccc1SC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.8 %

Procedure:
To 50B (12.0 g, 28.2 mmol) and triethylamine (7.86 mL, 56.4 mmol) in dichloromethane at −10° C. was added titanium chloride (113 mL, 1M in dichloromethane) dropwise under argon. The reaction was stirred at rt for 4 h and then quenched with saturated potassium carbonate. The mixture was filtered through Celite® and the aqueous layer was extracted with dichloromethane (2×). The organic extracts were combined, washed with brine and dried over sodium sulfate. The solvent was evaporated to give 7.3 g of crude pyrrolidine 50C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:19]3[CH2:20][CH2:21][CH2:22][CH:23]([OH:24])[C:18]=3[O:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[F:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOC(C)=O>[F:25][C:26]1[CH:31]=[CH:30][C:29]([O:24][CH:23]2[C:18]3[O:17][N:16]=[C:15]([C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[C:19]=3[CH2:20][CH2:21][CH2:22]2)=[CH:28][CH:27]=1
Reactant: Oc1ccc(F)cc1
Reactant: COc1cc(-c2noc3c2CCCC3O)ccc1-n1cnc(C)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(-c2noc3c2CCCC3Oc2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 50 °C
Yield: 43.2 %

Procedure:
To a mixture of 3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4,5,6,7-tetrahydrobenzo[d]isoxazol-7-ol (48 mg, 0.149 mmol) in THF (1.0 mL) was added 4-flurophenol (23 mg, 0.2 mmol), Ph3P (58 mg, 0.22 mmol) and DEAD (39 mg, 0.22 mmol). The reaction mixture was stirred over night at 50° C. The reaction mixture cooled, diluted with EtOAc, washed with water and brine, dried over MgSO4 and concentrated. The crude product was purified by preparative TLC using 5% MeOH in DCM as solvent to afford 27 mg of the title product.
Reaction SMILES: [CH2:1]([N:8]([C:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C1C=CC=CC=1.[CH2:30]([O:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=1)[CH3:31]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:8]([CH3:9])[C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:37]3[CH:38]=[CH:39][C:34]([C:33]([O:32][CH2:30][CH3:31])=[O:41])=[CH:35][CH:36]=3)=[CH:17][CH:18]=2)[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1ccc(C2(N(C)Cc3ccccc3)CC2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(N(C)Cc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Using General Procedure F; benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-methylamine (Intermediate 132, 70.0 mg, 0.28 mmol) and ethyl-4-iodo benzoate (Reagent A, 77.0 mg, 0.28 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (18.0 mg, 0.10 mmol) and sparged with argon for 5 minutes. Dichlorobis (triphenylphosphine)palladium(II) (65 mg, 0.10 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 86 mg (75%) of the title compound as an oil.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2Cl)(=O)C.[N:16]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[S:18][C:17]=1[NH2:25]>>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:25][C:17]1[S:18][C:19]2[C:24]([N:16]=1)=[CH:23][CH:22]=[CH:21][N:20]=2
Reactant: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Reactant: Nc1nc2cccnc2s1
Product: Oc1ccc2ncnc(Nc3nc4cccnc4s3)c2c1

Procedure:
The compound of Example 38 was manufactured using 6-acetoxy-4-chloro-quinazoline and thiazolo[5,4-b]pyridin-2-yl-amine by the same method as in Example 1 for the manufacture of 6-iodoquinazolin-4-yl)-thiazolo[5,4-b]pyridin-2-yl-amine, by a similar method thereto or by a combination of such a method with a conventional method.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:32])([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:9])[CH2:3]1.CN(C1C=CC=CN=1)C.[C:43](OC(=O)C)(=[O:45])[CH3:44]>C(Cl)(Cl)Cl.C(N(CC)CC)C.C(OCC)(=O)C>[F:33][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:32])([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:43](=[O:45])[CH3:44])=[CH:26][CH:25]=2)[C:8]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(OC(=O)[C@](O)(c2ccc(CO)cc2)[C@@H]2CCC(F)(F)C2)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1ccc([C@@](O)(C(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)[C@@H]2CCC(F)(F)C2)cc1
Temperature: 25 °C

Procedure:
To a solution of 42 mg of t-butyl 4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-(hydroxymethyl)phenyl)-ethanoyloxy)tetrahydropyridine-1(2H)-carboxylate in 2 ml of chloroform, 0.015 ml of triethylamine, 0.01 ml of acetic anhydride and 2 mg of dimethylaminopyridine were added successively, followed by an hour's stirring at room temperature. The reaction liquid was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified on preparative thin layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), hexane/ethyl acetate=2/1) to provide 42 mg of the title compound as a colorless oily substance.