Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:44])([CH3:43])[CH2:7][N:8]([S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][CH3:42])[CH:36]=1)(=[O:34])=[O:33])[CH2:9][C@@H:10]([OH:31])[C@@H:11]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.Cl[C:55]([O:57][CH3:58])=[O:56]>C1COCC1>[CH2:12]([C@H:11]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:10]([OH:31])[CH2:9][N:8]([CH2:7][C:6]([CH3:44])([CH3:43])[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:55]([O:57][CH3:58])=[O:56])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][CH3:42])[CH:36]=1)(=[O:34])=[O:33])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCCN)c1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCCNC(=O)OC)c1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A solution of 55 mg (0.087 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-3-((6-amino-2,2-dimethylhexyl)[3-(methylamino)phenyl]sulfonylamino)-1-benzyl-2-hydroxypropyl]carbamate and 17.0 μL (0.091 mmol) of N,N-diisopropylethylamine in 4 mL of anhydrous THF at 0° C. was treated with 7.0 μL (0.091 mmol) of methyl chloroformate. The solution was allowed to warm to RT with stirring. After 18 hours the solution was concentrated in vacuo and the residue was subjected to flash chromatography (SiO2, 95:5 CH2Cl2/2M NH3 in MeOH) to afford 55 mg (92%) of the desired compound as a white foam. H1-NMR (CDCl3): 7.34-7.12 (m, 6H), 7.02 (d, 1H), 6.94 (s, 1H), 6.78 (d, 1H), 5.60 (d, 1H), 5.17 (d, 1H), 5.02-4.70 (m, 2H), 4.14 (s, 1H), 4.02 (m, 1H), 3.89 (dd, 1H), 3.79 (m, 2H), 3.72-3.55 (m, 5H), 3.28-2.91 (m, 6H), 2.83 (s, 3H), 2.89-2.64 (m, 3H), 1.65-1.18 (m, 8H), 0.91 (s, 3H), 0.88 (s, 3H). MS (ESI): 691 (M+H).
Reaction SMILES: [NH2:1][C:2]1([C:14]([OH:16])=[O:15])[CH2:7][CH2:6][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH3:21]O>>[NH2:1][C:2]1([C:14]([O:16][CH3:21])=[O:15])[CH2:7][CH2:6][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:4][CH2:3]1
Reactant: CO
Reactant: COC1(C(F)(F)F)CCC(N)(C(=O)O)CC1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(N)CCC(OC)(C(F)(F)F)CC1

Procedure:
12.20 g (corresponds to about 37.58 mmol) of 1-amino-4-methoxy-4-(trifluoromethyl)cyclohexanecarboxylic acid (Example 18A) were suspended in 210 ml of methanol, and 10.4 ml (142.80 mmol) of thionyl chloride were added at 0° C. The mixture was boiled under reflux for 2 hours and cooled, another 10.4 ml (142.80 mmol) of thionyl chloride were added at 0° C. and the mixture was boiled under reflux for a further 2 hours. The reaction was cooled, another 10.4 ml (142.80 mmol) of thionyl chloride were added and the mixture was heated at reflux overnight until the reaction had gone to completion. For work-up, about 100 ml of methanol were distilled off and the concentrate was poured into 1 l of saturated aqueous sodium carbonate solution. The product was extracted with ethyl acetate and the organic phase was dried over sodium sulphate. Concentration by evaporation gave 7.01 g (73% of theory) of the title compound as a yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)=[CH:8][CH:9]=1)=[O:4].C1CCC(N=C=NC2CCCCC2)CC1.[CH:40]1([C:43](O)=[O:44])[CH2:42][CH2:41]1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][N:13]([C:43]([CH:40]2[CH2:42][CH2:41]2)=[O:44])[CH2:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: O=C(O)C1CC1
Reactant: COC(=O)c1ccc(CCCNCc2ccc3c(c2)OCCO3)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCCN(Cc2ccc3c(c2)OCCO3)C(=O)C2CC2)s1
Yield: 102 %

Procedure:
A solution of 5-{3-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-propyl}-thiophene-2-carboxylic acid methyl ester (0.435 g, 0.125 mmol), DCC (0.0284 g 0.137 mmol) and cyclopropanecarboxylic acid (0.0119 g, 0.137 mmol) in 10 mL CH2Cl2 was stirred at room temperature for 16 h. The mixture was filtered and the mother liquor was concentrated in vacuo. The residue was dissolved in 15 mL EtOAc and was filtered. The organic solution was washed with water followed by brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound of Step B as an oil (53 mg). MS 416 (M+).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[C:15](I)[C:16]3[C:21]([CH3:23])([CH3:22])[C:20](=[O:24])[NH:19][C:17]=3[N:18]=2)=[N:6]1.[F:30][C:31]([F:35])([F:34])[CH2:32][NH2:33]>CN1C(=O)CCC1>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[C:15]([NH:33][CH2:32][C:31]([F:35])([F:34])[F:30])[C:16]3[C:21]([CH3:23])([CH3:22])[C:20](=[O:24])[NH:19][C:17]=3[N:18]=2)=[N:6]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)nc(I)c21
Reactant: NCC(F)(F)F
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)nc(NCC(F)(F)F)c21
Temperature: 170 °C

Procedure:
50 mg (0.09 mmol) of 2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 33A) was dissolved in 1 ml of absolute NMP and 336 mg (3.70 mmol) of 2,2,2-trifluoroethanamine was added. The mixture was heated in the microwave for 2 h at 150° C., 18 h at 150° C., 2 h at 160° C., 2 h at 170° C. and 5 h at 170° C. The reaction solution was filtered and purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→100:0). 18 mg (purity 88%, 36% of theor.) of the target compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](SC)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>C1C=CC=CC=1.C(OCC)(=O)C>[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:4]2[N:5]=[N:6][C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:2]([CH3:1])[N:3]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: O=C(c1ccco1)N1CCNCC1
Reactant: CSc1nnc(-c2ccccc2)c(C)n1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc(N2CCN(C(=O)c3ccco3)CC2)nnc1-c1ccccc1
Yield: 29 %

Procedure:
A mixture of 5-methyl-3-methylthio-6-phenyl-1,2,4-triazine (9 g) and N-(2-furoyl)piperazine (10 g) was heated at 150° to 160° C. for 89 hours with stirring. The reaction mixture was dissolved in benzene (300 ml) and subjected to chromatography on silica gel (300 g) using a mixture of benzene and ethyl acetate (3:2) as an eluent. The eluate was concentrated to dryness and the resulting solid was recrystallized from a mixture of chloroform and diisopropyl ether to give crystals of 3-[4-(2-furoyl)-1-piperazinyl]-5-methyl-6-phenyl-1,2,4-triazine (4.20 g), mp 141.5°~142.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([O-])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1.[Na+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[N:6][CH:7]=1
Reactant: Nc1ccc([O-])c([N+](=O)[O-])c1
Reactant: Clc1ncc(Br)cn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(-c2ncc(Br)cn2)c([N+](=O)[O-])c1

Procedure:
1.94 g of 5-bromo-2-chloropyrimidine and 1.93 g of sodium 4-amino-2-nitrophenolate were dissolved in 20 ml of dimethylformamide, and reacted in the atmosphere of nitrogen gas at 150° C. for 5 hours. After the completion of the reaction, the reaction product was poured into water, and extracted with ethyl acetate. The extract layer was washed with brine and dried over anhydrous sodium sulfate, and purified by silica gel column chromatography, whereby 1.35 g of 4-(5-bromo-2-pyrimidinyl)-3-nitroaniline having a melting point of 165° to 167° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11](Cl)=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:14][C:15]1[N:20]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH2:19][N:18]=[C:17]2[O:28][CH:29]=[CH:30][C:16]=12>>[NH2:14][C:15]1[N:20]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:11]([C:8]3([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:10][CH2:9]3)=[O:12])=[CH:25][CH:26]=2)[CH2:19][N:18]=[C:17]2[O:28][CH:29]=[CH:30][C:16]=12
Reactant: O=C(Cl)C1(c2cccc(Cl)c2)CC1
Reactant: NC1=c2ccoc2=NCN1c1ccc(N)cc1
Product: NC1=c2ccoc2=NCN1c1ccc(NC(=O)C2(c3cccc(Cl)c3)CC2)cc1

Procedure:
The compound was prepared following the procedure described in Example 474, using 1-(3-chloro-phenyl)-cyclopropanecarbonyl chloride as the acid chloride of choice, and 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) as the diamine of choice. MS(ES) m/e 405 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2([C:13]([CH3:15])([CH3:14])[CH:12]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4]2[C:9]([C:10]=1[Cl:11])=[CH:8][CH:7]=[CH:6][CH:5]=2.CC(C)([O-])C.[K+].O>C(O)(C)(C)C>[Cl:11][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]([CH3:14])([CH3:15])[CH:12]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:2]=1
Reactant: CCOC(=O)C1C(C)(C)C12C(Cl)=C(Cl)c1ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)C1C(C)(C)C12C=C(Cl)c1ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A solution of 2',3'-dichloro-3,3-dimethyl-spiro[cyclopropane-1,1'-indene]-2-carboxylic acid-, ethyl ester (19 g as is, containing iodobenzene) in t-butanol (50 ml) is added to a 0.1 M solution of potassium-t-butoxide in t-butanol (450 ml; 0.045 mole) and the mixture allowed to stir overnight at room temperature. The reaction mixture is then poured into water, extracted with ether, the ether extracts dried over magsium sulfate and evaporated to dryness to afford 11.1 g of a black oil. This oil is purified by chromatography (silica gel; eluent: 1:1 mixture of methylene chloride:hexane), to afford 2 g of title product, a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][OH:10]>[O-2].[O-2].[Mn+4].CC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]=[O:10]
Reactant: Nc1ccc(Br)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: Nc1ccc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 71.1 %

Procedure:
To acetone (300 ml)were added (2-amino-5-bromophenyl)methanol (23.32 g) and active manganese dioxide (58.5 g), and the mixture was stirred at room temperature for 17.5 hours and filtered. The solvent was evaporated under reduced pressure to give 2-amino-5-bromobenzaldehyde (16.41 g, 71%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]#[N:16])=[CH:5][C:4]=2[NH:3]1.[Br:17]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:17][C:13]1[S:14][C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:15]#[N:16])=[CH:5][C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc2c(c1)[nH]c(=O)c1ccsc12
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)[nH]c(=O)c1cc(Br)sc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carbonitrile (1.0 eq, 350 mg, 1.55 mmol) was mixed with N-bromosuccinimide (1.1 eq, 303 mg, 1.70 mmol) in acetic acid (4 ml). The mixture was stirred at 100° C. for 4 hours. The mixture was cooled down to 80° C., more NBS (303 mg) was added and the mixture stirred overnight. Water was added and the material filtered and dried. Trituration in methanol and filtration afforded 2-bromo-4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carbonitrile as a grey solid (396 mg, 84% yield). LCMS (ES)>80% pure, m/z 305 [M]+, 307 [M+2]+.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[O:13]1[C:17]2([CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.O>C1COCC1>[N:10]1[CH:11]=[CH:12][C:7]([C:20]2([OH:23])[CH2:21][CH2:22][C:17]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:18][CH2:19]2)=[CH:8][CH:9]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2ccncc2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
n-BuLi (32 ml, 64.0 mmol, 2 eq, 2 M solution in hexane) was placed in THF (60 ml) and cooled to −78° C. A solution of 4-bromopyridine (6.3 g, 40.0 mmol, 1.25 eq) in THF (50 ml) was slowly added dropwise at that temperature, and stirring was carried out for 1.5 h. A solution of 1,4-dioxaspiro[4.5]decan-8-one (5.0 g, 32.0 mmol, 1 eq) in THF (50 ml) was added likewise at −78° C., and stirring was carried out for 2 h. After monitoring by thin-layer chromatography, the reaction solution was hydrolyzed with water (100 ml), while cooling, and extracted with ethyl acetate (2×200 ml). The combined organic phases were washed with water (100 ml) and sat. NaCl solution (100 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 2% MeOH in dichloromethane), the desired product was obtained in the form of a light-brown solid. Yield: 64% (6.0 g, 25.53 mmol).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24](SC)=[N:25][CH:26]=2)[CH:15]=1>O>[Br:1][C:2]1[C:3]([CH2:9][S:10][CH2:11][CH2:12][NH:13][C:24]2[NH:23][C:22](=[O:29])[C:21]([CH2:20][C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)=[CH:26][N:25]=2)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccnc(CSCCN)c1Br
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Solvent: O
Product: Cc1ccnc(CSCCNc2ncc(Cc3cccnc3)c(=O)[nH]2)c1Br

Procedure:
2-(3-Bromo-4-methyl-2-pyridylmethylthio)ethylamine (1.5 g) and 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone (1.0 g) were fused together at 160°-170° for 1 hour. The cool mixture was taken up in water at pH 2 and extracted with chloroform. The aqueous phase was adjusted to pH 7 and extracted with chloroform, and the chloroform extract was evaporated and the residue purified chromatographically on silica gel (eluting with chloroform/ammoniacal methanol 50:1) to give the title compound, m.p. 81°-85°
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:21])[CH:14]([CH2:17][CH2:18][CH2:19][Cl:20])[CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]([OH:21])[CH:14]([CH2:17][CH2:18][CH2:19][Cl:20])[CH2:15][CH2:16][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1c2c(-c3ccc(Cl)cc3)noc2C=CC1CCCCl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1c2c(-c3ccc(Cl)cc3)noc2CCC1CCCCl
Temperature: -5 °C
Reaction time: 0.75 h
Yield: 98.8 %

Procedure:
In 100 ml of anhydrous THF was dissolved 6.0 g 3-(4-chlorophenyl) -5-(3-chloropropyl)-1,2-benzisoxazol-4(5H)- one under nitrogen atmosphere. The solution was cooled to -5° C. and 840 mg sodium borohydride was added. The reaction mixture was stirred at 0° C. for 45 minutes and then warmed to 10° C. for 20 minutes. After cooling to 0° C., the reaction mixture was quenched with aqueous NH4Cl (saturated) then extracted with ether. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 6.0 g of 3-(4-chlorophenyl)-5-(3-chloropropyl)-4-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole as an oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[C@H:31]([OH:33])[CH3:32].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=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>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=2)=[C:25]([C@H:31]([OH:33])[CH3:32])[CH:26]=1
Reactant: C[C@@H](O)c1cc(Cl)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](O)c1cc(Cl)ccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Yield: 74537.5 %

Procedure:
A vigorously stirred mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,2,3-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1-4) (34.0 g, 0.110 mol), (1R)-1-(2-bromo-5-chlorophenyl)ethanol (3-4) (25.8 g, 0.110 mmol), potassium phosphate tribasic (70.0 g, 0.330 mol) and tetrakis(triphenylphosphine)palladium(0) (2.54 g, 2.20 mmol) in N,N-dimethylformamide (440 mL) was degassed via three vacuum/nitrogen ingress cycles and then heated at 100° C. for approximately 18 h. After cooling to room temperature, the reaction mixture was poured into ice/water (˜1:1) and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (25% ethyl acetate/hexanes as eluent) afforded 3-5 (27.7 g) as a pale yellow foam.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28]/[C:29](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[N:30]\[O:31][CH3:32]>C(#N)C.O>[CH3:32][O:31]/[N:30]=[C:29](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CO/N=C(\CBr)c1ccccc1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCc1ccc(-c2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Temperature: 80 °C
Yield: 60 %

Procedure:
To a solution of ethyl 3-(4′-hydroxybiphenyl-4-yl)propanoate (0.27 g, 0.001 mmol) in acetonitrile was added potassium carbonate (0.27 g, 0.002 mmol) and (1Z)-2-bromo-N-methoxy-1-phenylethanimine (0.23 g, 0.001 mmol) and refluxed at 80° C. for 3 h. RM was diluted with water and extracted with ethyl acetate, Organic layer was washed with water and brine solution, dried over anhydrous Na2SO4 and concentrated to get crude product which was purified by comb flash to get white gummy solid as product (0.25 g, Yield: 60%): MS (ESI, 120 eV): m/z=418 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 7.59-7.63 (m, 2H), 7.37-7.42 (m, 4H), 7.26-7.28 (m, 3H), 7.15 (d, 2H), 6.88-6.90 (d, 2H), 5.15 (s, 2H), 4.03-4.10 (m, 2H), 3.99 (s, 3H), 2.87-2.93 (t, 2H), 2.54-2.60 (t, 2H), 1.17-1.19 (t, 3H).
Reaction SMILES: [Li+].[CH3:2][Si]([N-][Si](C)(C)C)(C)C.[O:11]=[C:12]1[O:16][C@@H:15]([C:17]([Cl:20])([Cl:19])[Cl:18])[N:14]2[CH2:21][CH2:22][CH2:23][C@:13]12[CH:24]=O>C1COCC1>[Cl:18][C:17]([Cl:20])([Cl:19])[C@H:15]1[N:14]2[CH2:21][CH2:22][CH2:23][C@:13]2([CH:24]=[CH2:2])[C:12](=[O:11])[O:16]1
Reactant: O=C[C@]12CCCN1[C@H](C(Cl)(Cl)Cl)OC2=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C[C@]12CCCN1[C@H](C(Cl)(Cl)Cl)OC2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
The solution of CH3P(Ph)3Br (268 mg, 0.736 mmol) in anhydrous THF (5 mL) was cooled to −78° C. under N2. LiHMDS (1 M in THF, 0.69 mL) was added dropwise via syringe. The mixture was stirred at 0° C. for 1 h then cooled down to −78° C. again. To it, was added the reactant carbaldehyde 155b (125 mg, 0.46 mmol) in anhydrous THF (5 mL) at −78° C. dropwise. The mixture was stirred at −78° C. to RT over 2 h period, then RT for 2 h. Reaction was monitored by TLC. After completion, the reaction was quenched by adding sat'd NH4Cl. It was extracted with EtOAc twice, washed with brine. The organic layer was dried through (Na2SO4), and concentrated; the residue was purified by CombiFlash on silica gel column using EtOAC/Hexane as eluents to give (3S,7aS)-3-(trichloromethyl)-7a-vinyltetrahydropyrrolo[1,2-c]oxazol-1(3H)-one 30 mg, 24%.
Reaction SMILES: O1CCCC1.[H-].C([Al+]CC(C)C)C(C)C.CON(C)[C:19]([C:21]1[N:22]=[CH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20]>CCCCCCC>[CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[C:21]([CH:19]=[O:20])[N:22]=1
Reactant: CON(C)C(=O)c1cc2ccccc2cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: O=Cc1cc2ccccc2cn1
Temperature: -78 °C

Procedure:
In 5 mL dry tetrahydrofuran 0.11 g (0.52 mmol) of isoquinoline-3-carboxylic acid methoxy-methyl-amide was dissolved, and cooled down to −78° C. under the atmosphere of nitrogen. 0.57 mL of 1M diisobutylaluminum hydride solution in heptane was added slowly. After the addition was complete, the solution was allowed to warm up to 0° C. over 2 hours and was quenched with ethyl acetate, and water was added, and extracted with dichloromethane. The organic solution was dried with anhydrous magnesium sulfate and evaporated in vacuum to give 60 mg of the crude aldehyde, which was used in the following steps without purification. LC-MSD, m/z for C10H7NO [M+H]+: 158.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29][CH2:28]4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2cccc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(Cc2cccc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
21A (52 mg, 0.089 mmoL) was dissolved in a mixture of TFA/DCM (2 ml/2 ml) and stirred at rt for 10 min, then concentrated. The residue was purified by prep HPLC to give 21B (38 mg, 88%). It has an analytical HPLC retention time=1.93 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=482+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[N:5][N:4]=[N:3]1.[NH2:16][C:17]([NH2:19])=[S:18].[OH-].[Na+]>ClCCCl.CCOCC>[CH3:1][N:2]1[C:6]([C:7]2[S:18][C:17]([NH2:19])=[N:16][C:8]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1CC(=O)c1ccccc1
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCCl
Product: Cn1nnnc1-c1sc(N)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
2-(1-Methyl-1H-tetrazol-5-yl)-1-phenyl-ethanone (4.9 g, 24.2 mmol) was dissolved in 1,2-dichloroethane (150 mL) and ether (100 mL). Brom (1.24 mL, 24.2 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. the solvent was removed in vacuo. The remenance was dissolved in ethanol (250 mL). Thiourea (3.67 g, 48.5 mmol) was added and the reaction mixture was heated at reflux for 20 min. The reaction mixture was poured into water/ice. Concentrated NaOH (aq) was added until pH=10. The mixture was filtered and the solid product was recrystallised from ethylacetate/hexane. Yield: 58%.