Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:24])[NH:12][CH2:13][C:14]2[NH:15][C:16]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][C:58]1=[O:63].ClCl>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:60]1[CH2:61][CH2:62][N:57]([CH3:56])[C:58](=[O:63])[CH2:59]1)=[O:6])[C:11]([NH:12][CH2:13][C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=2[N:15]=1)=[O:24]
Reactant: O=C(NCc1nc2ccc(Cl)cc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CN1CCNCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)CC1=O
Yield: 8.7 %

Procedure:
Prepared analogously to Example 19c from 2-chloro-4-[N-(5-chlorobenzimidazol-2-ylmethyl)carbamoyl]benzoic acid, TBTU, diisopropylethylamine, and N-methylpiperazinone in N,N-dimethylformamide. Yield: 8.7%; C21H19Cl2N5O3 (460.32); mass spectrum: (M+H)+=460/462/464 (chlorine isotope).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:22])[N:11]=[N:12][C:13]=2[C:14]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16](Cl)[CH:15]=2)=[CH:4][CH:3]=1.[NH:23]1[CH2:26][CH2:25][CH2:24]1>>[N:23]1([C:16]2[CH:15]=[C:14]([C:13]3[N:12]=[N:11][C:10]([NH2:22])=[N:9][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:19]=[C:18]([CH3:20])[N:17]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: C1CNC1
Reactant: Cc1cc(-c2nnc(N)nc2-c2ccc(F)cc2)cc(Cl)n1
Product: Cc1cc(-c2nnc(N)nc2-c2ccc(F)cc2)cc(N2CCC2)n1
Yield: 3.7 %

Procedure:
6-[2-(azetidin-1-yl)-6-methylpyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (6.0 mg, 4%) was prepared from 5-(4-fluorophenyl)-6-(2-chloro-6-methyl-pyridin-4-yl)-1,2,4-triazin-3-amine (150 mg, 0.48 mmol) and azetidine (136 mg, 0.16 ml, 2.38 mmol) according to the general procedure for Preparation 4a.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:10]3[CH:27]=[N:26][N:25]([CH2:28][CH3:29])[C:11]=3[N:12]=[CH:13][C:14]=2[C:15]2[CH2:19][C:18]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[O:17][N:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:37](Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>ClCCl>[CH:2]1([NH:8][C:9]2[C:10]3[CH:27]=[N:26][N:25]([CH2:28][CH3:29])[C:11]=3[N:12]=[CH:13][C:14]=2[C:15]2[CH2:19][C:18]3([CH2:24][CH2:23][N:22]([C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:21][CH2:20]3)[O:17][N:16]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCNCC4)C3)cnc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCN(C(=O)C(C)(C)C)CC4)C3)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
N-Cyclohexyl-1-ethyl-5-(1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride salt (70 mg, 0.00016 mole) (example 22) was taken in dichloromethane (10 ml). Triethyl amine (0.07 ml, 0.00050 mole) and pivaloyl chloride (0.030 ml, 0.00025 mole) were added at 0° C. The reaction mixture was stirred at room temperature overnight. It was diluted with dichloromethane, washed with sodium bicarbonate solution, extracted with brine, dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product obtained was purified by preparative thin layer chromatography.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[S:28](N)([NH2:31])(=[O:30])=[O:29]>O1CCOCC1>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@H:2]4[NH:1][S:28]([NH2:31])(=[O:30])=[O:29])[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NS(N)(=O)=O)no2)cc1C#N
Temperature: 110 °C
Reaction time: 14 h
Yield: 25.8 %

Procedure:
Prepared using General Procedure 22: To a stirred solution of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (50 mg, 0.14 mmol) in dioxane (1.5 mL) was added sulfamide (66 mg, 0.69 mmol) and the mixture was heated to 110° C. After 14 h of stirring, the solvent was evaporated and the residue was purified by column chromatography. Additional purification by recrystallization from MeOH provided 15.9 mg (26%) of (R)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamide 248. LCMS-ESI (m/z) calculated for C21H21N5O4S: 439.5. found 440.1 [M+H]+, tR=3.42 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.1 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 8.13 (d, J=7.6 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 5.08 (dd, J=16.1, 7.9 Hz, 1H), 4.80 (dt, J=12.1, 6.1 Hz, 1H), 4.65 (s, 1H), 4.59 (d, J=8.4 Hz, 1H), 3.50 (ddd, J=17.5, 8.8, 3.7 Hz, 1H), 3.30-3.09 (m, 1H), 2.87-2.67 (m, 1H), 2.07 (dt, J=21.3, 8.2 Hz, 1H), 1.47 (t, J=6.3 Hz, 6H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[S:10][C:11]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([OH:20])=O)[C:12]=2[N:13]=1)=[O:7].[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl.O>[C:21]1([N:27]2[CH2:32][CH2:31][N:30]([C:18]([CH:14]3[C:12]4[N:13]=[C:9]([NH:8][C:6]([C:2]5[O:1][CH:5]=[CH:4][CH:3]=5)=[O:7])[S:10][C:11]=4[CH2:17][CH2:16][CH2:15]3)=[O:20])[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Nc1nc2c(s1)CCCC2C(=O)O)c1ccco1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1nc2c(s1)CCCC2C(=O)N1CCN(c2ccccc2)CC1)c1ccco1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1,1-Carbonyldiimidazole (CDI, 0.31 g, 1.9 mmol) was added to a solution of 2-[(furan-2-carbonyl)amino]-4,5,6,7-tetrahydrobenzthiazol-4-carboxylic acid (0.5 g, 1.7 mmol) in CH2Cl2 (10 mL), and the resultant mixture was stirred for a period of 2 hours at room temperature. Following cooling of the suspension to 0° C., N-phenylpiperazine (0.28 g, 1.73 mmol), dissolved in CH2Cl2 (10 mL), was added dropwise over a period of 5 minutes. After stirring for 30 min at 0° C. and overnight at room temperature, there were added a few drops of water. Following drying over Na2SO4 and filtration, the solvent was removed and the residue was purified via column chromatography. The product furan-2-carboxylic acid(4-(4-phenylpiperazin-1-carbonyl)-4,5,6,7-tetrahydrobenzthiazol-2-yl]amide was obtained in a yield of 514 mg (corresponding to 69% of the theoretical yield).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:6][CH2:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[CH2:4][OH:5].[C:13]([N:17]=[C:18]=[S:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(O)C>[C:13]([NH:17][C:18]([NH:2][C@H:3]([CH2:6][CH2:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[CH2:4][OH:5])=[S:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: N[C@@H](CO)CCc1ccsc1
Reactant: CC(C)(C)N=C=S
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=S)N[C@@H](CO)CCc1ccsc1
Temperature: 20 °C

Procedure:
A solution of 1.2 g of (2R)-2-amino-4-(3-thienyl)-1-butanol, hydrochloride in 40 mL of ethanol, is combined with 1.1 mL of tert-butylisothiocyanate and 1 mL of triethylamine and magnetically stirred under inert atmosphere at a temperature of about 20° C., then heated for 20 hours at a temperature of about 50° C. The reaction medium is concentrated under reduced pressure (2 kPa) at a temperature of about 50° C. The solution is evaporated to obtain a residue, which is purified by chromatography under argon pressure (70 kPa), on a column of silica gel (particle size 60-200 μm; diameter 3.6 cm; height 20 cm), eluting with a mixture of cyclohexane-ethylacetate (60/40 by volume) and obtaining fractions of 30 mL. The fractions containing the expected product are collected and evaporated under reduced pressure (2 kPa) at a temperature of about 40° C. About 0.73 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(2-thien-3-ylethyl)ethyl]thiourea are obtained in the form of a colorless oil. [1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm): 1.42 (s, 9H); from 1.60 to 1.95 (mt, 2H); 2.60 (t large, J=8 Hz, 2H); 3.38 (mt, 1H); 3.50 (mt, 1H); 4.26 (mf, 1H); 4.80 (mf, 1H); 7.01 (dd, J=5 and 1.5 Hz, 1H); from 7.15 to 7.25 (mt, 2H); 7.20 (s, 1H); 7.46 (dd, J=5 and 3 Hz, 1H)].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:13][C:14]1C=C(C)C=CC=1S([O-])(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#[N:32].[K+].C1OCCOCCOCCOCCOCCOC1.[I-].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:13][C:14]#[N:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])c(C[C@@H](NC(=O)OCc2ccccc2)c2ccccc2)c1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
60.5 g of ((R)-2-benzyloxycarbonylamino-2-phenylethyl)-4-methylphenylsulphonate (142.2 mmol) are dissolved in 675 ml of dimethylformamide. 13.9 g of potassium cyanide (213.3 mmol), 5.64 g of 18-crown-6 (21.33 mmol) and 520 mg of potassium iodide (3.13 mmol) are added and the mixture is stirred at 50° C. for 20 hours. The reaction solution is poured into 500 ml of ice water and this mixture is subsequently stirred at 0° C. for 5 hours. The mixture is filtered with suction and the precipitate is dissolved in ethyl acetate. The organic phase is washed three times with water, dried over magnesium sulphate and concentrated in vacuo. The residue is triturated with diethyl ether, filtered off with suction, washed with diethyl ether and dried over phosphorus pentoxide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([OH:12])[CH2:6][C:5]1([CH3:14])[CH3:13].[C:15](OC(=O)C)(=[O:17])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:15]([O:1][CH2:2][CH2:3][N:4]1[C:5]([CH3:14])([CH3:13])[CH2:6][CH:7]([OH:12])[CH2:8][C:9]1([CH3:10])[CH3:11])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CC(O)CC(C)(C)N1CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCCN1C(C)(C)CC(O)CC1(C)C
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Into a 250 ml flask equipped with a magnetic stirbar, thermometer, addition funnel and nitrogen atmosphere was placed 1-(2-hydroxyethyl)-2,2,6,6-tetramethyl-4-piperidinol (10.0 g, 0.499 mole) and 75 ml of methylene chloride. The resulting slurry was cooled to -20° C. and the addition funnel wash charged with acetic anhydride (5.1 g, 0.496 mole) and 15 ml of methylene chloride. The anhydride was added dropwise to the diol slurry with no apparent reaction. The mixture was warmed to 15° C. at which temperature the solids began to dissolve. The mixture was stirred at ambient temperature for 2 hours. The mixture was poured into 80 ml of 10% sodium carbonate (aqueous) and stirred for 15 minutes at ambient temperature. The mixture was transferred to a separatory funnel and extracted with 100 ml of methyl t-butyl ether. The ether solution was dried with anhydrous magnesium sulfate and the solvent removed using aspirator and high vacuum systems. The product was a white solid melting at 56°-58° C. This material was used without further purification.
Reaction SMILES: [OH:1][C@H:2]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:21]Br.O>CC(O)=O>[Br:21][C:18]1[S:17][C:16]([C@@H:2]([OH:1])[C@@H:3]2[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:20][CH:19]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1cccs1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To 0° C. solution of (±)-(4R*,5R*)-5-((1S*)-hydroxy-2-thienylmethyl)-1-methyl-4-phenylpyrrolidin-2-one (9.76 g, 34 mmol) in AcOH (246 mL) was added bromine (2 mL 38.8 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 2 h, then poured into water (500 mL). The resulting mustard colored precipitate was isolated via filtration and washed with water to yield (±)-(4R*,5R*)-5-[(1S*)(5-bromo(2-thienyl))hydroxymethyl]-1-methyl-4-phenylpyrrolidin-2-one (6.47 g, 52%): mp 105° C.; TLC (EtOAc) Rf 0.48.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2].Br.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:24]=2[Cl:23])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1csc(Nc2ccc(OC)c(OC)c2)n1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(OC)c(OC)c2)n1

Procedure:
A mixture of 2.18 g (7.1 mmol) 2-(3,4-Dimethoxy-phenylamino)-thiazole-4-carboxylic acid ethyl ester; hydrobromide, 2.24 g (10.7 mmol) 2,4-Dichlorobenzoyl chloride and 2.96 ml (21.4 mmol) NEt3 in 30 ml DCM was stirred at room temperature for 24 h. After evaporation of the volatiles the residue was taken up in MeOH and purified with flash column chromatography on silica eluting with a gradient of heptane/ethyl acetate to yield after evaporation of the product fractions 0.75 g (22%) of the title compound. MS (m/e): 481.1 (MH+, 100%)
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH:10]1[C:22]2[CH:21]([CH2:23][O:24][C:25]([NH:27][C@@H:28]([CH2:32][CH2:33][NH2:34])[C:29]([OH:31])=[O:30])=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH:19]1[C:20]2[CH:21]([CH2:23][O:24][C:25]([NH:27][C@@H:28]([CH2:32][CH2:33][NH:34][C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:6])[C:29]([OH:31])=[O:30])=[O:26])[C:22]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cl)C1CCC1
Reactant: NCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CCNC(=O)C1CCC1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclobutanecarbonyl chloride (69.7 mg, 0.588 mmol) and NaOH (0.705 mL, 0.705 mmol) were dropped at the same time to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-aminobutanoic acid (200 mg, 0.588 mmol) in THF (1.5 mL) and of NaOH (1N, 0.7 mL) at 0° C. The reaction mixture was allowed to stir at rt for 1 h at which time LC-MS showed desired product peak. The reaction solution was acidified with 1N HCl and extracted with EtOAc (60 mL×1). The crude was purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to provide the title compound (92.6 mg, 37%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:22](Cl)(Cl)=[S:23]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]=[C:22]=[S:23])=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(Oc2nccnc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: S=C=Nc1ccc(Oc2nccnc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(3-chloropyrazin-2-yloxy)benzenamine (620 mg, 2797 μmol) and sodium carbonate (652 mg, 6154 μmol) in chloroform (10 ml) was added thiophosgene (236 μl, 3077 μmol). The solution turned cloudy and was stirred overnight at room temperature. The solvent had evaporated so the residue was taken back up in chloroform and the solids were removed by filtration. The filtrate was collected and the solvent was removed by roto-vap to give the desired product as a brown solid which was used without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([Si:15](Cl)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].[CH2:21]([Si:23]([O:28][C:29](=[O:39])[CH2:30][O:31][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])([CH2:26]C)[CH2:24]C)C>C1COCC1>[CH2:13]([Si:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[O:39][C:29]([O:28][Si:23]([CH3:26])([CH3:24])[CH3:21])=[CH:30][O:31][Si:32]([CH2:37][CH3:38])([CH2:33][CH3:34])[CH2:35][CH3:36])[CH3:14]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC[Si](CC)(CC)OCC(=O)O[Si](CC)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC[Si](CC)(CC)OC=C(O[Si](C)(C)C)O[Si](CC)(CC)CC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (15.5 mL, 0.11 mol) in THF (100 mL) at −78° C. was added a 1.6 M hexanes solution of n-butyl lithium (70 mL, 0.11 mol) over 15 minutes. After stirring for an additional 15 minutes at this temperature, triethylsilylchloride (16.7 mL, 0.1 mol) was added over 10 minutes followed by the addition of triethylsilyl-2-(triethylsiloxy)acetate (37.6 g, 0.1 mol) over 30 minutes. The reaction was stirred at −78° C. for 30 minutes and warmed to ambient temperature by removing the cryogenic bath and the THF solvent was removed by vacuum rotary evaporation at 40° C. to precipitate the lithium chloride. The mixture was taken up in 300 mL of hexanes and 5 mL of triethylamine and stirred for 5 minutes and the salt was allowed to settle. The supernatant was twice filtered through a pad of diatomaceous earth to give a clear solution. The solution was concentrated under rotary evaporation to give the lightly yellow colored oil product as a 1:1 mixture of geometrical isomers.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:16][O:15][CH2:14][C@H:13]([CH3:17])[O:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([O:1][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)OC)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(F)cc2)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of methyl 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate (3.53 g, 14.7 mmol), p-fluoro-phenyl-boronic acid (16.2 mmol), copper(II) acetate (2.94 g, 16.2 mmol), triethylamine (10.3 ml, 73.5 mmol) and freshly activated 4 A molecular sieves (17.7 g) in dichloromethane was stirred at ambient temperature and under ambient atmosphere for 2 days. The reaction mixture was filtered, and the dichloromethane was removed in vacuo. The residual oil was partitioned between ethyl acetate and 2 mol/l hydrochloric acid. The ethyl acetate layer was separated, washed with aqueous sodium hydrogen carbonate and brine, dried over Na2SO4 and evaporated to give a residue, which was purified by column chromatograph on silica gel (20-60% ethyl acetate in iso-hexane, gradient) to give the desired ester.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][C@@H:7]([CH3:10])[CH2:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:20]([S:23](Cl)(=[O:25])=[O:24])([CH3:22])[CH3:21]>C(Cl)Cl>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][C@@H:7]([CH3:10])[CH2:8][NH:9][S:23]([CH:20]([CH3:22])[CH3:21])(=[O:25])=[O:24])=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: C[C@@H](CN)Oc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC[C@H](C)Oc1ccc(Br)cc1
Temperature: 0 °C

Procedure:
The above prepared (2S)-2-(4-bromophenoxy)propylamine was combined in a 500 mL 3-neck round bottomed flask with triethylamine (5.7 mL) and methylene chloride (110 mL), fitted with a thermometer, stirbar, and in a nitrogen system. The reaction mixture was cooled to 0° C. in an ice bath, with stirring, and isopropylsulfonyl chloride (2.75 mL, 24.585 mmol) was added by syringe. The mixture was stirred overnight, gradually becoming room temperature. The reaction was quenched with 100 mL water, and extracted two times with 100 mL methylene chloride. The organic extractions were combined, and washed with 200 mL brine, dried with sodium sulfate, filtered and concentrated in-vacuo, yielding 2.08 g viscous brown oil. This material was further purified using one Waters Prep-Pak® on a Waters Prep 2000 HPLC, in a 3:1 hexanes:ethyl acetate solvent system to provide the final title compound (1.63 g, 30%) as a viscous yellow oil.
Reaction SMILES: [NH2:1][C:2]([CH3:7])=[CH:3][C:4](=O)[CH3:5].CO[C:10]1(OC)[CH2:14][CH2:13][CH2:12][N:11]1[CH3:15].C(O[Na])(C)(C)C.CC(O)(C)C>C1(C)C=CC=CC=1>[CH3:15][N:11]1[C:10]2=[N:1][C:2]([CH3:7])=[CH:3][C:4]([CH3:5])=[C:14]2[CH2:13][CH2:12]1
Reactant: COC1(OC)CCCN1C
Reactant: CC(=O)C=C(C)N
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: Cc1cc(C)c2c(n1)N(C)CC2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution containing 1.20 g (12.1 mmol) of 4-amino-3-penten-2-one in 8 mL of toluene was added 3.00 g (20.7 mmol) of 2,2-Dimethoxy-1-methylpyrrolidine. The reaction mixture was heated at reflux and stirred for 2 h, cooled to 90° C., and then treated with 2.38 g (24.8 mmol) of t-BuONa and 2 mL of t-BuOH. The reaction mixture was stirred at 90° C. for another 16 h. The cooled reaction mixture was quenched by the addition of 10 mL of sat aq. NH4Cl. The mixture was extracted with three 30-mL portions of EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under diminished pressure. The residue was purified via flash chromatography on a silica gel column (42×2.5 cm). Step gradient elution with 1:4→1:1 ethyl acetate-hexanes as eluent gave 1,4,6-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine as a brown oil: yield 0.62 g (32%); silica gel TLC Rf 0.15 (1:4 ethyl acetate-hexanes); 1H NMR (CDCl3) 1.91 (s, 3H), 2.20 (s, 3H), 2.65 (t, 2H, J=8.4 Hz), 2.76 (s, 3H), 3.23 (t, 2H, J=8.4 Hz), 5.98 (s, 1H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]>O.C(OCC)C>[CH2:1]([NH:4][C:16](=[O:17])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5](=[O:7])[CH3:6])=[CH:14][CH:13]=1)[CH2:2][CH3:3]
Reactant: CC(=O)Oc1ccc(CC(=O)Cl)cc1
Reactant: CCCN
Solvent: O
Solvent: CCOCC
Product: CCCNC(=O)Cc1ccc(OC(C)=O)cc1
Temperature: 0 °C

Procedure:
To an ice-cold solution of 1-propylamine (9 g) in water (50 ml) was added solution of 4-acetoxyphenylacetyl chloride (10.6 g) in diethyl ether (100 ml), keeping the temperature of the mixture between 15° and 250° C. with external cooling. The ether layer was separated, washed with brine and evaporated to give N-(1-propyl)-4-acetoxyphenylacetamide as a pale yellow oil, essentially pure by TLC, which was used without further purification or characterisation.