Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([I:15])=[C:5]([C:10]([O:12]CC)=[O:11])[S:6][C:7]=1[S:8][CH3:9])#[N:2].[OH-].[Na+]>O1CCCC1.O>[C:1]([C:3]1[C:4]([I:15])=[C:5]([C:10]([OH:12])=[O:11])[S:6][C:7]=1[S:8][CH3:9])#[N:2]
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1sc(C(=O)O)c(I)c1C#N
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of ethyl 4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylate (3.40 g, 10 mmol) in tetrahydrofuran (80 mL) and water (16 mL) was added a solution of 1.00M sodium hydroxide in water (30 mL). The solution was allowed to stir overnight. The reaction was quenched with a solution of 1N hydrogen chloride in water (50 mL) and diluted with water (400 mL). The resultant precipitate was filtered, washed with water (2×100 mL) and dried in a vacuum oven to give 4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylic acid (2.6 g, 79%) as a white solid. LCMS: (FA) ES+ 326. 1H NMR (400 MHz, d6-DMSO) δ: 14.1-13.8 (bs, 1H), 2.75 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[C:25]([Cl:26])=[C:24]([OH:27])[CH:23]=[CH:22][C:19]=1[CH:20]=O>>[Cl:17][C:18]1[C:25]([Cl:26])=[C:24]([OH:27])[CH:23]=[CH:22][C:19]=1[CH:20]=[CH:15][C:14]([C:12]1[S:13][C:9]([C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)=[O:16]
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Reactant: CSc1ccc(-c2ccc(C(C)=O)s2)cc1
Product: CSc1ccc(-c2ccc(C(=O)C=Cc3ccc(O)c(Cl)c3Cl)s2)cc1

Procedure:
3-(2,3-Dichloro-4-hydroxyphenyl)-1-(5-(4-(methylthio)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(methylthio)phenyl)thien-2-yl)ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is used “as is” for carrying out the next stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]([CH3:13])[C:10](=[O:14])[CH:9]=[CH:8][C:7]=2[C:6]([CH:15]=O)=[CH:5][CH:4]=1.[C:17]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:15]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]([O:25][CH2:26][CH3:27])=[O:24])=[C:7]2[C:12]=1[N:11]([CH3:13])[C:10](=[O:14])[CH:9]=[CH:8]2
Reactant: COc1ccc(C=O)c2ccc(=O)n(C)c12
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C(=Cc1ccc(OC)c2c1ccc(=O)n2C)C(=O)OCC
Temperature: 95 °C
Reaction time: 6 h
Yield: 53 %

Procedure:
8-Methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-5-carboxaldehyde (18.9 g), diethyl malonate (26.5 ml) and piperidine (2.7 ml) were added to pyridine (90 ml), and the resulting mixture was stirred at 90 to 100° C. for 6 hours. After cooling to room temperature, the reaction mixture was added to cold concentrated hydrochloric acid, and the precipitated solid was collected by filtration, washed with water and dried to thereby obtain 16.62 g (yield: 53%) of diethyl 2-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-ylmethylene)malonate as a yellow powder.
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-:35][Si](C)(C)C)(C)C>O1CCCC1>[C:24]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20](=[NH:35])[NH2:21])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N#Cc1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N=C(N)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 16 h
Yield: 83.4 %

Procedure:
A solution of EXAMPLE 12A (0.515 g, 1.36 mmol) in dry tetrahydrofuran (6 mL) was treated dropwise with LiHMDS (1M, 6.8 mL, 6.8 mmol), stirred for 16 hours, quenched with 1N HCl (8 mL), and filtered. The filter cake was collected to provide the desired product (0.45 g, 71%) that was used without further purification. MS (CI) m/e 397 (M+H)+.
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[N:14]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:26]([N:14]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]1[C:6]([OH:7])=[O:5])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@@H]2CCCC[C@H]2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@@H]2CCCC[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
To a solution of 1.364 g (2.97 mmol) of the product from Example 5 in 10 mL of dichloromethane was added 10 mL of trifluoroacetic acid and the mixture was stirred for 4 h at room temperature. The solvent was then concentrated in vacuo and the residue was chromatographed on silica gel eluting with 10-100% ethyl acetate/hexane to provide 1.092 g (73%) of the desired product as a white solid. Electrospray Mass Spec 404.2 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=3)[N:15]=[C:14]2[CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[NH2:44][C:45]1[C:50]([C:51]#[N:52])=[C:49](Cl)[N:48]=[CH:47][N:46]=1>C(#N)C>[NH2:44][C:45]1[N:46]=[CH:47][N:48]=[C:49]([N:32]2[CH2:33][CH2:34][CH:29]([C:14]3[N:13]([CH:10]4[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]4)[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:27])([F:26])[F:28])[CH:19]=4)[N:15]=3)[CH2:30][CH2:31]2)[C:50]=1[C:51]#[N:52]
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCNCC2)C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCN(c3ncnc(N)c3C#N)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[4-(4-fluoro-3-trifluoromethyl-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (109.27 mg; 0.23 mmol; 1.00 eq.) in acetonitrile 2 ml was added ethyl-diisopropyl-amine (0.08 ml; 0.45 mmol; 2.00 eq.) and 4-amino-6-chloro-pyrimidine-5-carbonitrile (35.00 mg; 0.23 mmol; 1.00 eq.), the reaction mixture was stirred at RT for 1 hr, lc-ms showed desired as major product, removed off solvent, got residue, which as title compound directly using for the next step reaction.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:17])[C:5]([C:8]1[CH:9]=[CH:10][C:11]([F:16])=[C:12]([CH:15]=1)[C:13]#[N:14])([CH3:7])[CH3:6].CCN(CC)CC.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[S:34])=[CH:28][C:27]=1[O:35][CH3:36]>C(Cl)Cl>[C:13]([C:12]1[CH:15]=[C:8]([C:5]([CH3:7])([CH3:6])[C:4](=[O:17])[CH2:3][NH:2][C:33]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[C:27]([O:35][CH3:36])[CH:28]=2)=[S:34])[CH:9]=[CH:10][C:11]=1[F:16])#[N:14]
Reactant: COc1cc(N=C=S)ccc1F
Reactant: CC(C)(C(=O)CN)c1ccc(F)c(C#N)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=S)NCC(=O)C(C)(C)c2ccc(F)c(C#N)c2)ccc1F
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a suspension of 5-(4-amino-2-methyl-3-oxobutan-2-yl)-2-fluorobenzonitrile hydrochloride (2.8 g, 10.9 mmol) in DCM (50 mL) were added Et3N (4.6 mL, 32.7 mmol, 3 eq) and 1-fluoro-4-isothiocyanato-2-methoxybenzene (2.2 g, 12 mmol, 1.1 eq). After stirring 2 h, the reation mixture was partitioned in DCM and water. The organic layer was separated, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography (silica, Hex:EA=1:1) to give 1-(3-(3-cyano-4-fluorophenyl)-3-methyl-2-oxobutyl)-3-(4-fluoro-3-methoxyphenyl)thiourea (3.7 g, 84%). 1H NMR (400 MHz, CDCl3) δ 7.59 (bs, 1H), 7.53-7.49 (m, 2H), 7.26-7.18 (m, 2H), 6.89-6.79 (m, 2H), 6.70 (bs, 1H), 4.44 (d, J=4.4 Hz, 2H), 3.90 (s, 3H), 1.58 (s, 6H).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([CH3:13])=O)[C:6]([O:8]CC)=[O:7])C.Cl.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>C(O)C>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:11]([CH3:13])=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=[N:24]2)=[CH:19][CH:18]=1
Reactant: NNc1ccc(F)cc1
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Agent: Cl
Solvent: CCO
Product: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1
Yield: 47.5 %

Procedure:
To an ethanol (75 ml) solution of ethyl 2-(ethoxymethylene)acetoacetate (28.63 g) prepared according to a method described in J. Chem. Soc. Perkin trans. I, 1875 (1988), was added 1N hydrochloric acid aqueous solution (75 ml) of 4-fluorophenylhydrazine hydrochloride (25 g) and the mixture was stirred at reflux temperature for three hours. After evaporation of ethanol, sodium hydroxide (12 g) was added to the residue and stirred at reflux temperature for three hours. After completion of the reaction, the solvent was evaporated, diluted hydrochloric acid was added to the residue, and the precipitated solid was washed with ethyl acetate to give the titled compound (16.08 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].Cl.[CH3:13]O>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:13])=[O:10]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1O
Agent: Cl
Product: COC(=O)Cc1ccccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
2-(Hydroxyphenyl)acetic acid (50 g) was added to a solution of hydrogen chloride in methanol [prepared from acetyl chloride (25 ml) and methanol (250 ml)]. The solution was stirred at room temperature for three hours and then allowed to stand overnight (fifteen hours). The resulting mixture was concentrated under reduced pressure, and the residue was taken up in ether (250 ml) and washed with an aqueous solution of sodium bicarbonate until effervescence ceased. The ethereal solution was dried and then concentrated under reduced pressure and the resulting solid was recrystallized from ether/petrol to afford methyl (2-hydroxyphenyl)acetate (50 g; 92% yield) as white, powdery crystals, top. 70°-72° C.; infrared max. (nujol mull): 3420, 1715 cm-1 ; 1H nmr (90 MHz): delta 3.70 (2H,s), 3.75 (3H,s), 6.80-6.95 (2H,m), 7.05-7.10 (1H,m), 7.15-7.25 (1H,m), 7.40 (1H, s) ppm.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-])=O)[CH:3]=1.Cl.[Sn](Cl)[Cl:17]>O>[ClH:17].[NH2:12][C:4]1[CH:3]=[C:2]([Br:1])[C:10]([F:11])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Cl[Sn]Cl
Reactant: O=C(O)c1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: Nc1cc(Br)c(F)cc1C(=O)O
Temperature: 90 °C
Yield: 83 %

Procedure:
To a mixture of 4-bromo-5-fluoro-2-nitrobenzoic acid (10 g, 37.9 mmol) and HCl (70 mL, 852 mmol) in water (70 mL) was added tin(II) chloride (21.55 g, 114 mmol) and the mixture was then heated at 90° C. for 3 hours. After cooling to RT, the formed precipitate was filtered, washed with water and collected to give title compound (8.51 g). LCMS (A): m/z [(M−HCl)+H]+ 234/236, C7H5BrFNO2.HCl requires 269/271 (acidic).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[N+:27]([C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33])([O-:29])=[O:28]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[N+:27]([O-:29])=[O:28])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
1.2 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in 10 ml of pyridine, and 0.66 g of 2-nitrobenzoyl chloride is added thereto. The mixture is stirred at room temperature for 2 hours. After the reaction, the mixture is poured into ice-water. The crystalline precipitates are collected by filtration and then recrystallized from a mixture of ethyl acetate and n-hexane. 1.41 g of (±)-cis-2-(4-methoxyphenyl)-3-(2-nitrobenzoyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are thereby obtained as colorless needles. Yield: 84%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]3[N:16]=[CH:17][CH:18]=[CH:19][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Br>CS(C)=O>[O:24]1[CH:22]([CH3:20])[CH:23]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]3[N:16]=[CH:17][CH:18]=[CH:19][C:10]=3[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1c(-c2ccc(O)cc2)nc2cccnc2c1=O
Reactant: BrCC1CO1
Solvent: CS(C)=O
Product: CC1OC1Oc1ccc(-c2nc3cccnc3c(=O)n2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.4 gm (0.037 mol) of 2-(4-hydroxy-phenyl)-3-methyl-3,4-dihydro-pyrido[2,3-e]-pyrimidin-4-one were dissolved in 100 ml of dimethylsulfoxide, and the solution was mixed, while stirring with 4.5 gm (0.04 mol) of potassium tert. butylate. After a clear solution was formed, 9.4 ml of epibromohydrin were added, and the reaction mixture was stirred for one hour at room temperature. Thereafter, it was poured into 600 ml of ice water, and the resulting crystalline product was suction-filtered off and dried at 40° C. in a vacuum shelf-drier.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:29])[CH3:28])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][C:20]([CH2:23]O)=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:32])=O>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:29])[CH3:28])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][C:20]([CH2:23][Cl:32])=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(CO)nc2[nH]1
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(CCl)nc2[nH]1
Yield: 95.5 %

Procedure:
A solution of {2-[5-(benzyloxy)-2-isopropoxyphenyl]-3H-imidazo[4,5-b]pyridin-5-yl}methanol (0.11 g) and thionyl chloride (0.1 g) in chloroform (10 ml) was heated under reflux for 3 hr. The reaction mixture was concentrated, and saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated to give the title compound (0.11 g, yield 96%) as colorless crystals. purity 85%. M+H: 408. 1H NMR (CDCl3) δ: 1.51 (6H, d, J=6.0 Hz), 3.97-4.15 (2H, m), 4.72-4.81 (1H, m), 5.16 (2H, s), 7.00-7.06 (1H, m), 7.07-7.12 (1H, m), 7.31-7.51 (6H, m), 8.07 (1H, d, J=7.9 Hz), 8.20 (1H, s).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[C:14]2[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([C:27](=[O:35])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:22][CH2:21]4)=[CH:16][S:17][C:13]=2[C:12]([CH:36]2[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]2)=[CH:11][N:10]=1>ClCCl>[C:29]1([CH2:28][C:27]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([C:15]4[C:14]5[C:9]([NH2:8])=[N:10][CH:11]=[C:12]([CH:36]6[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]6)[C:13]=5[S:17][CH:16]=4)=[CH:26][CH:25]=3)[CH2:21][CH2:22]2)=[O:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc(N)c3c(-c4ccc5c(c4)CCN5C(=O)Cc4ccccc4)csc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(C2CCNCC2)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
TFA (0.5 mL, 6.49 mmol) was added to a suspension of 1,1-dimethylethyl 4-{4-amino-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-7-yl}-1-piperidinecarboxylate (90 mg, 0.158 mmol) in Dichloromethane (DCM) (3.5 mL), and the mixture was stirred at room temperature under Nitrogen for 30 min. The reaction mixture was then concentrated in vacuo, taken up in DCM, and passed through a PL-HCO3 MP-resin cartridge, rinsing with more DCM. The filtrate was concentrated in vacuo. The solid (labeled 96-A1) was not quite pure enough for submission (impurities best visible by NMR), so the residue was purified by flash chromatography (Analogix, 24 g SiO2, DCM to 80/20/2 DCM/MeOH/NH4OH gradient over 30 minutes) to give 3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]-7-(4-piperidinyl)thieno[3,2-c]pyridin-4-amine (37 mg) as a white solid. LC/MS (ES) m/z=469 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.64-1.77 (m, 2H), 1.77-1.86 (m, 2H), 2.57-2.77 (m, 3H), 3.07 (d, J=12.13 Hz, 2H), 3.22 (t, J=8.34 Hz, 2H), 3.89 (s, 2H), 4.24 (t, J=8.59 Hz, 2H), 5.24 (br. s., 2H), 7.19-7.39 (m, 7H), 7.41 (s, 1H), 7.70 (s, 1H), 8.15 (d, J=8.34 Hz, 1H)
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])[CH:15]=3)[N:10]([C:24](=[O:32])[NH:25][C:26]3[S:27][C:28]([Cl:31])=[CH:29][N:30]=3)[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].Cl.[NH:34]1[CH2:37][CH2:36][CH2:35]1>>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([N:34]4[CH2:37][CH2:36][CH2:35]4)=[O:22])[CH:15]=3)[N:10]([C:24]([NH:25][C:26]3[S:27][C:28]([Cl:31])=[CH:29][N:30]=3)=[O:32])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(CCCCC(=O)O)cc12
Reactant: C1CNC1
Agent: Cl
Product: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(CCCCC(=O)N3CCC3)cc12

Procedure:
5-(1′-Acetyl-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-5-yl)pentanoic acid and azetidine hydrochloride
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Cl:19])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(I)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: ClCCc1ccc(I)cc1
Yield: 98.6 %

Procedure:
To a 500 mL round-bottomed flask equipped with dropping funnel, condenser and N2 inlet were added 307 g (124 mmol) 2-(4-iodophenyl)ethanol, 200 mL chloroform, and 10.0 mL (124 mmol) pyridine. A solution of 13.5 mL (186 mmol) thionyl chloride in 50 mL chloroform was added dropwise over 15 min, and the reaction then heated at reflux for 2 hr. The reaction was cooled, the solvent evaporated, and the residue taken up in ethyl acetate, washed with 1 N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and brine, dried, and evaporated. The resulting oil was chromatographed on silica gel using 20% ethyl acetate in hexane as eluant to afford 32.6 g (99%) of the product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:32]1[CH:37]=[CH:36][C:35]([C:38]2([NH2:41])[CH2:40][CH2:39]2)=[N:34][CH:33]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:41][C:38]5([C:35]6[CH:36]=[CH:37][N:32]=[CH:33][N:34]=6)[CH2:40][CH2:39]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2ccncn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccncn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.07 g, 0.173 mmol, 1.0 eq) and 1-(pyrimidin-4-yl)cyclopropanamine HCl (0.023 g, 0.173 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.087 g, 0.861 mmol, 5.0 eq) and BOP reagent (0.114 g, 0.257 mmol, 1.5 eq). The reaction mixture was stirred at r.t. overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic was dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 3% MeOH/CHCl3 as eluent and further purified by prep HPLC. Yield: 0.040 g (44.45%). 1H NMR (400 MHz, CD3OD): δ 9.03 (d, J=1.0 Hz, 1H), 8.61 (d, J=5.8 Hz, 1H), 8.04-7.94 (m, 2H), 7.91-7.83 (m, 2H), 7.72-7.64 (m, 2H), 7.57-7.45 (m, 2H), 7.43-7.37 (m, 1H), 7.34-7.24 (m, 2H), 2.96 (s, 3H), 2.37 (s, 3H), 1.90-1.81 (m, 2H), 1.57-1.49 (m, 2H). 19F NMR (376.51 MHz, CD3OD): δ −78.35 (TFA), −113.31. LCMS: (ES+) m/z=521.2 (M+H)+
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].[OH:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].C1CCN2C(=NCCC2)CC1>CC#N>[CH3:6][C:5]([CH3:7])=[CH:4][CH2:3][CH2:2][O:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)=CCCBr
Reactant: CC(C)(C)OC(=O)NO
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)=CCCONC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a solution of 5-bromo-2-methylpent-2-ene (1.33 mL, 10.0 mmol) in CH3CN (25 mL) was added tert-butyl hydroxycarbamate (2.0 g, 15.0 mmol) and DBU (4.5 mL, 30 mmol) at 0° C. and the reaction mixture stirred at r.t. for overnight. Quenched with saturated NH4Cl solution and extracted with brine. Combined organic layers washed with brine and dried over anhydrous Na2SO4, filtered and concentrated to provide yellow oil, which was purified by flash chromatography (50% EtOAc-hexane) to yield tert-butyl 4-methylpent-3-enyloxycarbamate (750 mg, 70%) as a viscous oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40 (s, 9H) 1.54 (s., 3H) 1.61 (s., 3H) 2.21-2.31 (m, 2H) 3.70-3.78 (m, 2H) 5.02-5.10 (m, 1H). MS (ES) [M+H] calculated for C11H22NO3, 216.15; found 216.10.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].Cl.[F:28][CH2:29][CH2:30][CH2:31][NH2:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:32][CH2:31][CH2:30][CH2:29][F:28])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCCCF
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=S)NCCCF)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanatotetrahydro-2H-pyran-2,4,5-triyl triacetate (0.850 g, 2.19 mmol) and 3-fluoropropylamine hydrochloride (0.251 g, 2.21 mmol) in DCM (10 mL), was added DIPEA (0.415 g, 4.00 mmol). The reaction mixture was stirred at room temperature for 30 min, and then concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography (EtOAc/hexanes, 2:1 in), affording (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-(3-fluoropropyl)thioureido)tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white solid (0.91 g, 88%).