Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13]CC)=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.CCO.O.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>[C:20]1([O:19][CH2:18][CH2:17][CH2:16][C:7]2[C:6]3[C:10](=[C:2]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:10][C:6]=4[C:7]#[C:8][CH3:11])[CH:3]=[CH:4][CH:5]=3)[NH:9][C:8]=2[C:11]([OH:13])=[O:12])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2ccccc12
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: O
Solvent: COCCOC
Product: CC#Cc1ccccc1-c1cccc2c(CCCOc3cccc4ccccc34)c(C(=O)O)[nH]c12

Procedure:
A suspension of EXAMPLE 1C (0.034 g, 0.075 mmol), EXAMPLE 420B (0.1 g, 0.68 mmol), tetrakis(triphenylphosphine)palladium (0.004 g, 0.006 mmol), and solution of Na2CO3 (2M, 0.5 ml, 1 mmol) in dimethoxyethane/EtOH/H2O (7/2/3) 3 mL was heated under microwave conditions at 150 C for 30 min. The reaction mixture was quenched with aq. HCl (1M, 0.4 mL) and product extracted with ethyl acetate (3×7 mL). The organic phases were filtered through a drying cartridge (MgSO4, Alltech Asoc., 2 g) and concentrated under reduced pressure. The crude product was purified by chromatography on SiO2 using 1% AcOH in EtOAc as eluent. 1H NMR (300 MHz, DMSO-d6) δ12.39 (br s, 1H), 10.28 (s, 1H), 8.25 (dd, 1H), 7.87 (d, 1H), 7.71 (d, 1H), 7.38-7.56 (m, 8H), 7.21 (d, 1H), 7.09 (dd, 1H), 6.89 (d, 1H), 4.20 (m, 2H), 3.38 (m, 2H), 2.24 (m, 2H), 1.91 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[N:4]=[C:5]([S:29][CH3:30])[C:6]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:39][CH3:40].O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:31])[N:4]=[C:5]([S:29][CH3:30])[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:39][CH3:40])=[C:22]([O:27][CH3:28])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(O)c(OC)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
After dissolving 500 mg of {2-(4-hydroxy-3-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 10 ml of DMF, 314 mg of potassium carbonate and 118 μl of iodoethane were added and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with water and saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (435 mg, isomeric mixture) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][S:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[Cl-:21].[Al+3].[Cl-:23].[Cl-].[C:25]1([CH3:31])C=CC=C[CH:26]=1.O>O1CCCC1>[Cl:21][C:26]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:3]2[C:4]3[CH2:9][CH2:8][S:7][CH2:6][C:5]=3[S:10][C:2]2=[N:1][C:25]=1[CH2:31][Cl:23]
Reactant: COc1ccc(C(=O)c2c(N)sc3c2CCSC3)cc1
Reactant: Cc1ccccc1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CCl)nc3sc4c(c23)CCSC4)cc1
Yield: 88.3 %

Procedure:
To a mixture of 2-amino-4,5-dihydro-3-(4-methoxybenzoyl)-7H-thieno[2,3-c]thiopyrane (9.557 kg), 1,3-dicholoroacetone (4.172 kg) in tetrahydrofuran (48,79 L) was added aluminum chloride (5.424 kg) divided in 4 portions. Then, the mixture was stirred under reflux for 4.5 hours and toluene (38.74 L) was added at 10° C. or lower, followed by dropwise addition of water (47.79 L). After addition of toluene (56.83 L), the mixture was stirred and the organic layer was separated, washed with water, saturated aqueous sodium bicarbonate solution and then water. The solvent was distilled off until the content became 34.61 kg. Methanol (57.34 L) was added dropwise thereto at about 25° C. The mixture was stirred at 5° C. for 1 hour and crystals deposited were filtered off to obtain the titled compound (11.055 kg, 88.3%). 1H (CDCl3) δ: 2.18 (2H, t, J=5.7 Hz), 2.68 (2H, t, J=5.7 Hz), 3.90 (5H, s), 4.94 (2H, s), 7.01 (2H, d, J=8.7 Hz), 7.16 (2H, d, J=8.7 Hz).
Reaction SMILES: CS[CH2:3][C:4](=[O:15])[C:5]([N+:12]([O-:14])=[O:13])=[C:6]1[NH:11][CH2:10][CH2:9][CH2:8][S:7]1.[CH3:16][CH2:17][C:18](Cl)=[S:19].[CH3:21]CCC[C:25](Cl)=[S:26].CCCC(Cl)=S>>[CH3:21][S:19][CH2:18][CH2:17][CH2:3][C:4](=[O:15])[C:5]([N+:12]([O-:14])=[O:13])=[C:6]1[NH:11][CH2:10][CH2:9][CH2:8][S:7]1.[CH3:16][S:26][CH2:25][CH2:3][C:4](=[O:15])[C:5]([N+:12]([O-:14])=[O:13])=[C:6]1[NH:11][CH2:10][CH2:9][CH2:8][S:7]1
Reactant: CSCC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Reactant: CCC(=S)Cl
Reactant: CCCCC(=S)Cl
Agent: CCCC(=S)Cl
Product: CSCCC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Product: CSCCCC(=O)C(=C1NCCCS1)[N+](=O)[O-]

Procedure:
In a similar manner, 3-(methylthio)-1-nitro-1-(tetrahydro-2H-1,3-thiazin-2-ylidene)-2-propanone (18) was prepared as a yellow solid, m.p.: 117.5°-119°, from methylthioacetyl chloride; 5-(methylthio)-1-nitro-1-(tetrahydro-2H-1,3-thiazin-2-ylidene)-2-pentanone (19) was prepared as a pale yellow solid, m.p.: 49°-49.5°, from 4-methylthiobutyryl chloride; 4-(methylthio)-1-nitro-1-(tetrahydro-2H-1,3-thiazin-2-ylidene)-2-butanone (20) was prepared as a yellow solid, m.p.: 42°-43° from 3-methylthiopropionyl chloride.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1.O>CN(C=O)C>[F:35][C:34]([F:36])([F:37])[C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([C:38]([F:41])([F:39])[F:40])[CH:31]=1)[CH2:27][N:3]1[CH2:8][CH2:7][CH:6]([CH:9]=[C:10]2[S:14][C:13](=[O:15])[N:12]=[C:11]2[NH:16][CH2:17][C:18]#[CH:19])[CH2:5][CH2:4]1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)SC1=CC1CCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added potassium carbonate (345 mg) and 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (198 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (164 mg).
Reaction SMILES: C(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:21][O:22][C:23](=[O:35])[C@@H:24]([CH2:33][OH:34])[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].[O:36]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37]1>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>[C:29]([O:28][C:26]([NH:25][C@H:24]([CH2:33][O:34][CH:37]1[CH2:38][CH2:39][CH2:40][CH2:41][O:36]1)[C:23]([O:22][CH3:21])=[O:35])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: C1=COCCC1
Reactant: COC(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@@H](COC1CCCCO1)NC(=O)OC(C)(C)C
Yield: 95.3 %

Procedure:
To a 2 L three neck flask fitted with a magnetic stirbar, under argon, was added CH2Cl2 (500 mL), PPTs (pyridinium-p-toluene sulfonate) (2 g, 0.008 mol). After dissolving the PPTs by stirring, N-(tert-butoxycarbonyl)-D-serine methyl ester 1 (97.9 g, 0.446 mol) was added to give a clear yellow solution. DHP (3,4-dihydro-2H-pyran) (105 mL, 1.16 mol) was added in one portion. The clear yellow solution was stirred at room temperature over 60 hr to give a slightly cloudy yellow mixture. The mixture was evaporated to give an off-white solid. Ethyl acetate (650 mL) was added to the residue and stirred for 20 minutes to dissolve. The solution was washed with 1.2M HCl (1×500 mL) to pH 4, sat. NaHCO3 (1×600 mL plus 1λ300 mL) to pH 7, brine (1×500 mL), dried over MgSO4 (20 g), filtered and concentrated under reduced pressure to give 129 g (96%) of product 2 as a waxy white solid. 1H NMR (60 MHz, CDCl3) δ 5.2-5.7 (br m, 1H), 3.4-4.8 (m, 9H), 1.4-1.8 (m, 15H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[C:21]([C@:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:29])[CH2:27][OH:28])[CH:20]=[CH:19]3)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=NN=N1.[O:43]1CCCC1.C(N(CC)[P:51]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])C.OO>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[C:21]([C@:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:29])[CH2:27][O:28][P:51]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])([O:57][C:58]([CH3:59])([CH3:60])[CH3:61])=[O:43])[CH:20]=[CH:19]3)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)c1ccc2cc(Sc3cccc(OCc4ccccc4)c3)ccc2c1
Reactant: C1CCOC1
Reactant: CCN(CC)P(OC(C)(C)C)OC(C)(C)C
Agent: OO
Agent: c1nnn[nH]1
Product: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1ccc2cc(Sc3cccc(OCc4ccccc4)c3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
To a solution of (R)-tert-butyl 2-(6-(3-(benzyloxy)phenylthio)naphthalen-2-yl)-1-hydroxypropan-2-ylcarbamate (20.0 mg, 0.0000388 mol) and 1H-tetrazole (30.4 mg, 0.000434 mol) in tetrahydrofuran (2 mL, 0.02 mol) was added di-tert-butyl N,N-diethylphosphoramidite (60.1 μL, 0.000216 mol) at room temperature. The resulting mixture was stirred at room temperature overnight, then hydrogen peroxide (180 μL, 0.0017 mol) was added and the mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated. Na2S2O3, then extracted with EtOAc, and dried over Na2SO4. The residue was chromatographed with MeOH—CH2Cl2 (0-20%) to give (R)-tert-butyl 2-(6-(3-(benzyloxy)phenylthio)naphthalen-2-yl)-1-(di-tert-butoxyphosphoryloxy)propan-2-ylcarbamate as a gel (28 mg, 100%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH2:9])=[O:8].[CH2:10]1[CH:12]([CH:13](O)C#[N:15])[CH2:11]1>>[CH:12]1([CH2:13][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[C:7]([NH2:9])=[O:8])[CH2:10][CH2:11]1.[NH3:15]
Reactant: NC(=O)[C@H]1CCCCN1
Reactant: N#CC(O)C1CC1
Product: N
Product: NC(=O)C1CCCCN1CC1CC1

Procedure:
The title compound was prepared by a similar method to preparation 57 from (2R)-2-piperidinecarboxamide [see preparation 68] and cyclopropylcarboxaldehye. The crude compound was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (92:7:1) as the eluant to afford the product as a white solid, (44%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:31](=[O:39])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:39])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C(=O)Cl
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(=O)OC(C)(C)C)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (50 mg, 0.13 mmol) and tert-butyl 2-chloro-2-oxoacetate (0.064 mL, 0.40 mmol) [prepared according to G. Bucher at al, Eur J Org Chem, 545-552 (2001); b.p. 54-55° C., 21 mmHg]. Yield 44 mg (66%).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([CH3:16])[CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[F:15])[O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(CBr)c1
Temperature: 0 °C
Yield: 65.2 %

Procedure:
A mixture of tert-butyl(4-fluoro-3-methylphenoxy)dimethylsilane (step 1, 30 g, 0.12 mol), N-bromosuccinimide (24 g, 0.13 mol) and benzoylperoxide (1.5 g, 6.2 mmol) in carbon tetrachloride (75 mL) was reflux under nitrogen atmosphere for 4 h. The reaction mixture was cooled at 0° C., and the white precipitate was filtered. The filtrate washed with sodium bicarbonate aqueous solution, dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane to afford 25 g (65%) of the title compound as a colorless oil:
Reaction SMILES: [C:1]([N:6]=[C:7]=[O:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].C[C:10]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].[CH:20]1C=CC=CC=1>ClC(Cl)C>[C:1]([NH:6][C:7](=[O:8])[O:19][C:17]1[CH:18]=[CH:10][C:11]([C:12]([O:14][CH3:20])=[O:13])=[CH:15][CH:16]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: c1ccccc1
Reactant: Cc1cc(O)ccc1C(=O)O
Reactant: C=C(C)C(=O)N=C=O
Solvent: CC(Cl)Cl
Product: C=C(C)C(=O)NC(=O)Oc1ccc(C(=O)OC)cc1

Procedure:
A solution of methacryloyl isocyanate (11.1 g; 100 mmol) in dichloroethane (22 g) and methyl p-hydroxybenzoic acid (15.0 g; 100 mmol) were added to benzene (30 g), and the resultant mixture was heated at 80° C. under reflux for 60 minutes. The solvent was removed by evaporation under reduced pressure to give p-methoxycarbonylphenyl N-methacryloylcarbamate as crude crystals. Recrystallization from a mixture of hexane and chloroform gave colorless prisms. M.P., 98°-100° C.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C1CCCCC1.CCCCCCC>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:1][CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CCCCCCC
Solvent: C1CCCCC1
Solvent: CCCCCCC
Product: CC=CCCCCC
Product: CCCCCCCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.12 mmoles of (η5-cyclopentadienyl)titanium trichloride (CpTiCl3; Aldrich commercial product), 20 ml of anhydrous cyclohexane, 0.03 ml of a solution of n-dibutylglima 0.45 M in anhydrous cyclohexane and 0.54 ml of 1 molar Mg(butyl)2 in n-heptane (atomic ratio Mg/Ti=4.5), are charged into a tailed test-tube equipped with a magnetic stirrer, in an atmosphere of argon. The mixture is left under stirring for 20 hours at room temperature (the solution takes on an extremely dark colouring). 18.8 ml of 1-octene (distilled and maintained on molecular sieves) are added. At this point the solution is siphoned in an autoclave previously maintained under argon and the same procedure is carried out as described in example 1 above. At the end it is cooled to room temperature. About 18 ml of octane and 0.4 ml of 2-octene are obtained by distillation (GC, mass GC and NMR analyses). The results and process conditions are summarized in table 1 below.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[O:27]1[CH2:32][CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>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.C1COCC1>[O:27]1[CH2:28][CH:29]=[C:30]([C:2]2[CH:3]=[C:4]3[C@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:21]5[CH:22]=[N:23][CH:24]=[N:25][CH:26]=5)[CH:13]=4)[O:8][C:5]3=[N:6][CH:7]=2)[CH2:31][CH2:32]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1ncc(Br)cc12
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: [K+]
Solvent: C1CCOC1
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1ncc(C3=CCOCC3)cc12
Reaction time: 5 h

Procedure:
A 10-20 mL microwave vial was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (503 mg, 1.098 mmol), pyrimidin-5-ylboronic acid (143 mg, 1.153 mmol), pd(ph3p)4 (127 mg, 0.110 mmol). The vial was flushed with Ar(g), then THF (5489 μL, 1.098 mmol) and potassium carbonate (1.5 M) (1464 μL, 2.195 mmol) (aq. solution) were added in sequence. The vial was sealed and heated at 110° C. for 2 hours. The mixture was diluted with water and extracted with 10% i-PrOH/EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 100-g SNAP column, eluting with 0-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to provide (S)-3-bromo-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as an off-white solid. Step 2: A vial was charged with (S)-3-bromo-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (68.1 mg, 0.166 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (105 mg, 0.498 mmol), tetrakis(triphenylphosphine)palladium (19.18 mg, 0.017 mmol), THF (830 μL), and potassium carbonate (415 μL, 0.830 mmol) (as a 2.0 M aq. solution). The vial was sealed and placed in a 110° C. for 5 hours. The layers were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 25-g SNAP column, eluting with 0-60% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to give (S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a white solid
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>CN(C=O)C>[C:16]1([NH:15][CH2:2][C:3]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])=[O:4])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1ccccc1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 2-(N-Bromoacetylamino)benzoic acid from Example 79 (5.0 g, 19.37 mmol), aniline (4.51 g, 4.41 mL, 48.4 mmol) and anhyd DMF (50 mL) was heated in an oil bath at 85° C. for 4.5 h. The reaction mixture was cooled and poured into ice-water (500 mL). A solution of 50 KOH (100 mL) was added to dissolve the milky white suspension and the resulting homogenous solution was extracted with CH2Cl2 (200 mL, 2×100 mL). The combined CH2Cl2 extract was set aside and the aqueous layer was acidified to pH=3 (pH meter) with 5% HBr. The resulting precipitate was washed with 5% HBr solution and water, and then dried in a vacuum oven at 50° C. for 2 days, yielding 4.74 g (90.6%) of a white powder, mp 192.4-192.8° C. (sealed tube); 1H NMR (DMSO-d6) δ 13.41 (bs, 1H), 12.01 (s, 1H), 8.72 (d, J=8.4, 1H), 7.93 (dd, J=7.6, J=1.6, 1H), 7.59 (dt, J=8.8, J=1.6, 1H), 7.15-7.05 (m, 3H), 6.63-6.45 (m, 4H); 3.83 (s, 2H); 13C NMR (DMSO-d6) δ 170.85, 169.01, 148.11, 140.56, 134.13, 131.10, 128.94, 122.63, 119.38, 117.10, 115.96, 112.40, 48.93; MS (EI, m/z) 270.1 (M+)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C@@H:6]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17])[CH2:7][CH2:8][CH3:9])[CH3:2].[C:19](C1NC=CN=1)(C1NC=CN=1)=[O:20]>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C@@H:6]([N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:19]1=[O:20])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CCC[C@@H](CC(=O)OCC)Nc1ccccc1N
Solvent: C1CCOC1
Product: CCC[C@@H](CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reaction time: 12 h
Yield: 97.4 %

Procedure:
To a solution of (S)-3-(2-Amino-phenylamino)-hexanoic acid ethyl ester (650 mg, 2.6 mmol) in THF (10 mL) was added carbonyl diimidazole [CDI] (842 mg, 5.2 mmol) at room temperature under nitrogen atmosphere. The solution was stirred at the same temperature for 12 hours. The solution was concentrated and the residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product (S)-3-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (700 mg, 98%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]([NH2:29])([CH3:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=[CH2:32]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:26]([NH:29][CH2:32][CH2:31][C:30]([O:34][CH3:35])=[O:33])([CH3:27])[CH3:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: CC(C)(N)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: C=CC(=O)OC
Solvent: ClCCl
Product: COC(=O)CCNC(C)(C)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 100 °C

Procedure:
2-(3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-propan-2-amine (0.081 g, 0.20 mmol) and methyl acrylate (0.18 mL, 2.00 mmol) were combined in a sealed tube and heated neat at 100° C. for 1 day, during which LC-MS indicated completion of reaction. The cooled reaction mixture was diluted with CH2Cl2 and washed with aqueous saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. ISCO purification with 5% to 25% EtOAc/Hexanes afforded methyl 3-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)propan-2-ylamino)propanoate as a white amorphous solid. MS (ESI) m/z: Calculated: 489.2; Observed: 490.1 (M++1).