Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11](=[O:14])[C:12](=[O:13])[N:4]([C:5]=23)[CH2:3][C:2]1=[O:15].C1COCC1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>C(OCC)C>[OH:14][C:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]2[C:5]3[N:4]([CH2:3][C:2](=[O:15])[NH:1][C:10]=3[CH:9]=[CH:8][CH:7]=2)[C:12]1=[O:13]
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CN2C(=O)C(=O)c3cccc(c32)N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1CN2C(=O)C(O)(c3ccccc3)c3cccc(c32)N1
Reaction time: 8 h

Procedure:
A suspension was prepared from 4.3 g. of 1H-pyrrolo[1,2,3-de]quinoxalin-2,5,6(3H)-trione in 200 ml. of THF. 16 ml. of a 2.83 M phenylmagnesium bromide solution in diethyl ether (phenyl Grignard reagent) were added thereto while maintaining the temperature in the range 10°-15° C. The resulting reaction mixture was stirred overnight after which time, 200 ml. of a saturated aqueous amonium chloride solution were added. An additional 1500 ml. of diethylether were added and the ethereal layer decanted from the solids. The ethereal layer was dried and the ether removed therefrom in vacuo. The resulting residue, comprising 6-hydroxy-6-phenyl-1H-pyrrolo[1,2,3-de]quinoxalin-2,5(3H,6H)-dione melted at 259°-62° C. with decomposition after recrystallization from methanol; yielded = 2.4 g.
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([Br:9])[S:4][C:3]=1[C:10]([NH2:12])=O.C1(C)C=CC=CC=1.COC(OC)[N:23]([CH3:25])C.C(O)(=O)C.O.[NH2:33]N>>[Br:9][C:5]1[S:4][C:3]([C:10]2[NH:12][CH:25]=[N:23][N:33]=2)=[C:2]([Br:1])[C:6]=1[C:7]#[N:8]
Reactant: NN
Reactant: COC(OC)N(C)C
Reactant: N#Cc1c(Br)sc(C(N)=O)c1Br
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(Br)sc(-c2nnc[nH]2)c1Br
Temperature: 90 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
3,5-Dibromo-4-cyanothiophene-2-carboxamide (5.90 g, 19.0 mmol) was suspended in dry Toluene (250 mL, 2300 mmol). 1,1-Dimethoxy-N,N-dimethylmethanamine (10.1 mL, 76.1 mmol) was added and the mixture was heated to 90° C. for 1 hour. The mixture was cooled to rt then rotavaped to dryness to give a crude intermediate. The intermediate was suspended in acetic acid (150 mL, 2600 mmol). Hydrazine hydrate (5.78 mL, 76.1 mmol) was added dropwise and the temperature was raised to 55° C. The mixture was stirred at the same temperature for 2 hours. The suspension was then evaporated to remove most of acetic acid. The resulting solid was collected by filtration and dried under vacuum to give a product (5.54 g, yield 87.2%). LCMS: (FA) ES−, 331, 333, 335. 1H NMR (300 MHz, d6-dmso) δ: 14.2 (s, br, 1H), 8.65 (s, 1H).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]([C:11]#[N:12])=[C:7]([C:9]#N)[N:8]=1)[CH2:2][CH3:3].[CH2:32]([Mg]Br)[CH3:33].C([O:38]CC)C>>[C:11]([C:6]1[N:5]([C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:4]([CH2:1][CH2:2][CH3:3])=[N:8][C:7]=1[C:9](=[O:38])[CH2:32][CH3:33])#[N:12]
Reactant: CCCc1nc(C#N)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOCC
Reactant: CC[Mg]Br
Product: CCCc1nc(C(=O)CC)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Following a procedure similar to that described in Preparation 15, but using 8.05 g of 2-propyl-1-tritylimidazole-4,5-dicarbonitrile (prepared as described in Preparation 14) and 14 ml of a 3M solution of ethylmagnesium bromide in diethyl ether, 7.03 g of the title compound were obtained as crystals, melting an 96° C. (softening at 87° C.).
Reaction SMILES: C(NCCCCO[C:11]1([O:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH2:22][CH2:21][CH:20]=[CH:19][CH2:18][CH2:17][CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1)(=O)C=C.[C:33]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42]C1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2(C)O)C1)(=[O:36])[CH:34]=[CH2:35]>>[C:29]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][O:23][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]1[O:42][CH2:41][CH2:40][CH2:39][CH2:38][NH:37][C:33](=[O:36])[CH:34]=[CH2:35])(=[O:32])[CH:30]=[CH2:31]
Reactant: C=CC(=O)NCCCCOC1(OCCCCNC(=O)C=C)CCC=CCCC=CCCC1
Reactant: C=CC(=O)NCCCCOC1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2(C)O)C1
Product: C=CC(=O)NCCCCOC1CCCCCCCCCCC1OCCCCNC(=O)C=C

Procedure:
1,2-(Bis(4-acrylamidobutoxy)-5,9-cyclododecadiene; 3-(4-Acrylamidobutoxy)-17-methyl-5-androsten-17-ol;
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]([Cl:14])=[CH:5][CH:6]1[CH:8]([C:9]([OH:11])=[O:10])[C:7]1([CH3:13])[CH3:12].CCCCCCC.Br[CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1>O.C(#N)C.N12CCN(CC1)CC2>[Cl:3][C:4]([Cl:14])=[CH:5][CH:6]1[CH:8]([C:9]([O:11][CH2:23][C:24]2[CH:25]=[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[CH:28][CH:29]=2)=[O:10])[C:7]1([CH3:12])[CH3:13]
Reactant: BrCc1cccc(-c2ccccc2)c1
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Agent: C1CN2CCN1CC2
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: CC#N
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OCc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 54.1 %

Procedure:
Potassium hydroxide (2.0 g, 0.032 mole) was dissolved in 7 ml of water. To this solution was added 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid (6.6 g, 0.032 mole), which may be prepared according to the method of Farkas, et al., loc. cit. After dissolution, 100 ml of heptane was added, and the mixture was heated under reflux using a DeanStarke trap to remove the water from the mixture. The dry mixture was then cooled to 60°, and a solution of 3-bromomethylbiphenyl (7.5 g, 0.032 mole) and 0.1 g of 1,4-diazabicyclo[2.2.2]octane in 60 ml of acetonitrile was added. 3-Bromomethylbiphenyl may be prepared according to the method of M. Gomberg and J. C. Pernert, J. Am. Chem. Soc., 48, 1372 (1926) and H. O. Huisman, et al., Rec. Trav. Chim., 71, 899 (1951). The mixture was then heated under reflux for 5.5 hours. After cooling to room temperature, the reaction mixture was contacted with 100 g of ice in a separatory funnel, and when the ice had melted the phases were separated. The aqueous phase was saturated with sodium chloride before being extracted twice with 100 ml portions of heptane. The heptane extracts and the organic phase were combined, and the combined organic phase was washed with one 200 ml portion of a saturated sodium chloride solution. The solvent was removed from the organic phase using a rotary evaporator, leaving an oily, straw-colored residue weighing 9.9 g. The oil was distilled in a short path, air-bath heated Kugelrohr distillation apparatus at a pressure of 0.25 mm. After removing low boilers from the oil at a temperature below 145°, [1,1'-biphenyl]-3-ylmethyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate (6.5 g, 54.4% yield) was obtained at a temperature of 165°-175°.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:14][C:15]1([CH3:41])[CH:19]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])[N:18]2[C:28](=[O:40])[CH:29]([NH:30][C:31](=[O:39])[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:17]2[S:16]1.O>C(N)=O>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:14][C:15]2([CH3:41])[CH:19]([C:20]([O:22][CH2:23][C:24]([Cl:25])([Cl:26])[Cl:27])=[O:21])[N:18]3[C:28](=[O:40])[CH:29]([NH:30][C:31](=[O:39])[CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C@H:17]3[S:16]2)=[N:4][N:3]=1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: Cc1nnc(S)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: NC=O
Solvent: O
Product: Cc1nnc(SCC2(C)S[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)OCC(Cl)(Cl)Cl)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.8 %

Procedure:
5-Methyl-1,3,4-thiadiazole-2-thiol (0.20 g) and sodium bicarbonate (0.85 g) were dissolved in formamide (7 ml). To this solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.54 g), and the mixture was stirred for 5 hours at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography on silica gel using chloroform as developing solvent to give oily 2,2,2-trichloroethyl 2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.20 g) from the third fractions each of which was separated into about 30 ml.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][C:10]=1[F:34])[O:6][CH2:7][CH3:8])C.C1COCC1.CO.O[Li].O>O>[F:15][C:14]1[CH:13]=[C:12]([OH:16])[CH:11]=[C:10]([F:34])[C:9]=1[CH:5]([O:6][CH2:7][CH3:8])[C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)C(OCC)c1c(F)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1F
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C(=O)O)c1c(F)cc(O)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of (RS)-[4-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-ethoxy-acetic acid ethyl ester (10.4 g) in a THF (50 ml), MeOH (50 ml) and H2O (20 ml) mixture was added LiOH.H2O (1.75 g) and it was stirred 2 h at 60° C. After cooling water (240 ml) was added and the solution was washed with TBME (240 ml). The aqueous layer was collected, TBME was added (240 ml) and the mixture was acidified with 1 N HCl sol. The aqueous layer was extracted with one more portion of TBME. The combined organic layers were dried (MgSO4) and the solvent was evaporated to obtained an oil. Solid (RS)-(2,6-difluoro-4-hydroxy-phenyl)-ethoxy-acetic acid (4.6 g, 95%) was obtained after addition of AcOEt, evaporation of it and drying on the high vacuum over night. Off-white solid. MS 231.1 ([M−H]−).
Reaction SMILES: [OH-].[Na+].O.NN.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([C:13](=O)[CH3:14])[CH:12]=1>C(O)COCCOCCO>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([CH2:13][CH3:14])[CH:12]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: CCc1cc(Br)ccc1O
Temperature: 170 °C
Yield: 89.5 %

Procedure:
Sodium hydroxide (1.4 g, 35 mmol) and hydrazine monohydrate (2.04 mL, 42 mmol) were added to a solution of 5′-bromo-2′-hydroxyacetophenone (3 g, 14 mmol) dissolved in triethylene glycol (17 mL). The reaction mixture was heated to 170° C. for 24 h and then partitioned between 1 N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography (0% to 10% EtOAc in hexanes) to give the title compound (2.52 g, 90%).
Reaction SMILES: [NH2:1][CH:2]1[CH:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C:10]2[CH:9]=[C:8]([OH:21])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:29](=O)([O:35]C(C)(C)C)[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>O1CCCC1>[C:31]([O:30][C:29](=[O:35])[NH:1][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][C:8]([OH:21])=[CH:7][CH:6]=2)[CH:11]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)c(Cl)c1

Procedure:
7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-ol (10.8 g) and triethylamine (14.01 mL, 101 mmol) were dissolved in dry tetrahydrofuran (200 mL). Di-tert-butyl carbonate (7.31 g, 33.5 mmol) was added in small portions at room temperature. The reaction mixture was stirred over night. The solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed with water (2×200 mL). The ethyl acetate solution of the crude product was dried (Na2SO4). The solvent was evaporated in vacuo and the crude product was used for the next step without further purification. Yield: 12.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[CH2:10][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:19])[N:13]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:10][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:19])[N:13]=1
Reactant: COc1ccc(Cl)c(CSc2nc(C)cc(O)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(O)nc(SCc2cc(O)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a solution of the 2-{[(2-chloro-5-methoxyphenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (1.0 g, 3.36 mmol) compound in anhydrous dichloromethane at 0° C., 1 M solution of boron tribromide (0.844 g, 3.36 mmol) was added. The reaction mixture was stirred at room temperature overnight. Then, the reaction mixture was quenched with sodium bicarbonate solution and the solid was filtered. The crude solid was purified by using dichloromethane and methanol (1:10) to provide the product 2-{[(2-chloro-5-hydroxyphenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (0.62 g, 65% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 4.34 (s, 2H), 5.98 (bs, 1H), 6.66 (d, J=8.8 Hz, 1H), 6.97 (s, 1H), 7.20 (d, J=8.8 Hz, 1H); M+283.06.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC[C:29]([NH2:31])=[O:30].C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH2:18][C:29]([NH2:31])=[O:30])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(CC(N)=O)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one (example 162, step 3) was reacted with iodoacetamide in the presence of potassium carbonate to give the title compound as a colorless foam, MS (ESI+): m/z=453.1 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)[C:16]([F:28])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:25]1([C:23]2[NH:22][N:21]=[C:20]([NH:19][C:17]3[C:16]([F:28])=[CH:15][N:14]=[C:13]([NH:11][C@H:9]([C:6]4[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=4)[CH3:10])[N:18]=3)[CH:24]=2)[CH2:27][CH2:26]1
Reactant: Fc1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc(F)c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cn1
Temperature: 180 °C
Yield: 242.5 %

Procedure:
A mixture of (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 93 mg), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoropyrimidin-4-amine (Method 16, 127 mg) and DIPEA (0.22 ml) in n-BuOH (2.5 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 180° C. for 6 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound as solid (435 mg). NMR 11.28 (s, 1H), 8.92 (s, 3H), 8.24 (s, 1H), 6.04 (s, 1H), 4.92-5.54 (m, 1H), 1.82-1.98 (m, 1H), 1.56 (d, 3H), 0.94-1.06 (m, 2H), 0.64-0.80 (m, 2H). m/z 395.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:7])[CH2:4][O:5][CH3:6].[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.O>C1C=CC=CC=1>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]2[NH:1][CH2:2][CH:3]([CH2:4][O:5][CH3:6])[O:7]2)=[CH:11][CH:10]=1
Reactant: COCC(O)CN
Reactant: O=Cc1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: O
Product: COCC1CNC(c2ccc(Cl)cc2)O1
Temperature: 25 °C

Procedure:
Twelve and six tenths (12.6) grams of 1-amino-3-methoxy-2-propanol and 16.9 grams of p-chlorobenzaldehyde were combined in 150 milliliters of benzene and heated to reflux under a modified Dean-Stark apparatus until about 2.5 milliliters of water were azeotropically removed. An additional 50 milliliters of benzene was distilled over and the mixture was cooled to room temperature and the volume was adjusted to 109.2 milliliters, so that 4 milliliters=1 gram of intermediate. Aliquots of this solution were used in subsequent reactions.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:3]=1[CH2:24][C:25]([O:27][CH3:28])=[O:26].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:39]1[CH2:43]OC[CH2:40]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[C:3]=1[CH:24]([CH2:40][CH2:39][CH3:43])[C:25]([O:27][CH3:28])=[O:26]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C(F)(F)F)cc1)CCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C(F)(F)F)cc1)CCC3
Yield: 70 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(4-trifluoromethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.114 g; 0.281 mmol), LHMDS 1N in THF (0.312 mL; 0.312 mmol), 1-iodopropane (0.046 mL; 0.472 mmol) in DMF (4 mL) for 3.5 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.088 g (70%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8](Br)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[C:14]([C:16]1[CH:17]=[C:18]([N:22]2[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]2[CH3:28])[CH:19]=[CH:20][CH:21]=1)#[CH:15]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([C:15]#[C:14][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]3[CH3:28])[CH:17]=2)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: C#Cc1cccc(-n2c(C)ccc2C)c1
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Product: CCOC(=O)c1c(C)nc(C#Cc2cccc(-n3c(C)ccc3C)c2)n1C

Procedure:
The title compound, MS: m/e=362.8 (M+H+), was prepared in accordance with the general method of example 1b from 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and 1-(3-ethynyl-phenyl)-2,5-dimethyl-1H-pyrrole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20](SC#N)[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][N:17]=1.[NH2:34][CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(N(CC)C(C)C)(C)C>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20]([NH:34][CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][N:17]=1
Reactant: NC1CCOCC1
Reactant: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(SC#N)n2)c(OC)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(NC3CCOCC3)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To the suspension of 0.92 g (2.0 mmol) of 4-(2,4-dimethoxybenzylamino)-3-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)benzonitrile in 40 mL anhydrous THF was added 0.22 g (2.2 mmol) 4-amino-tetrahydropyran, then 0.7 mL (4.0 mmol) N,N-diisopropylethylamine. The mixture was stirred at room temperature under Argon balloon for 16 hrs till HPLC showed the completion of reaction. The mixture became clear then. The orange-red solution was diluted with EtOAc, washed with brine twice, and then dried over Na2SO4. Solvents were removed under vacuum to give 1.0 g orange-yellow solid as the crude product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:27][CH:28]=O)[C:5]([O:25][CH3:26])=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:17]([CH:20]=3)[C:18]#[N:19])=[N:10][N:9]=2)[CH:7]=1.[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[C:18]([C:17]1[CH:20]=[C:13]([C:11]2[S:12][C:8]([C:6]3[C:5]([O:25][CH3:26])=[C:4]([CH2:27][CH2:28][N:30]4[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]4)[CH:3]=[C:2]([F:1])[CH:7]=3)=[N:9][N:10]=2)[CH:14]=[CH:15][C:16]=1[CH2:21][CH:22]([CH3:23])[CH3:24])#[N:19]
Reactant: O=C(O)C1CNC1
Reactant: COc1c(CC=O)cc(F)cc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1c(CCN2CC(C(=O)O)C2)cc(F)cc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21 %

Procedure:
To a solution of 5-{5-[5-fluoro-2-(methyloxy)-3-(2-oxoethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(2-methylpropyl)benzonitrile (D37) (75 mg) and 3-azetidinecarboxylic acid (37 mg) in dichloromethane (DCM) (15 mL) stirred at room temperature was added AcOH (0.15 mL). The reaction mixture was stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (58.2 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA/THF/MeCN for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated. The residue was purified by Mass Directed AutoPrep to give 1-{2-[3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-5-fluoro-2-(methyloxy)phenyl]ethyl}-3-azetidinecarboxylic acid (E15) (19 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 0.94 (6H, d), 1.99 (1H, m), 2.33 (1H, m), 2.67 (4H, m), 2.77 (2H, d), 3.17 (4H, m), 3.80 (3H, s), 7.47 (1H, dd), 7.68 (1H, d), 7.90 (1H, dd), 8.34 (1H, dd), 8.50 (1H, d). δF (DMSO-d6, 376 MHz): −117.2. MS (ES): C26H27FN4O3S requires 494. found 495.2 (M+H+).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:49]1[CH2:54][CH2:53][S:52][CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:49]3[CH2:54][CH2:53][S:52][CH2:51][CH2:50]3)=[O:25])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1CSCCN1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]c(C(=O)N3CCSCC3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), thiomorpholine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.