Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][CH2:10][OH:11])=[C:4]([F:12])[CH:3]=1.N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>ClCCl.CN(C)C1C=CN=CC=1>[C:19]([O:11][CH2:10][CH2:9][C:5]1[C:4]([F:12])=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[F:8])(=[O:21])[CH3:20]
Reactant: OCCc1c(F)cc(Br)cc1F
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.9 %

Procedure:
A solution of 2-(4-bromo-2,6-difluorophenyl)ethanol (1.392 mmol) in dichloromethane (2 mL) was treated with pyridine (4.00 mL), acetic anhydride (4.18 mmol), and 4-(dimethylamino)pyridine (0.070 mmol). The reaction was stirred at room temperature for three days. At this point, the reaction contents were concentrated to in vacuo to minimum volume. The material was diluted with water (50 mL) and was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aq sodium bicarbonate, twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a beige oil (330 mg, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.95 (s, 3 H) 2.91 (t, J=6.32 Hz, 2 H) 4.18 (t, J=6.44 Hz, 2 H) 7.47 (d, J=7.07 Hz, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C([O:19]/[C:20](/[CH3:27])=[CH:21]/C(OCC)=O)C>CO>[Br:1][C:2]1[CH:3]=[C:4](/[C:14](/[CH3:15])=[CH:21]/[C:20](=[O:19])[CH3:27])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(=O)c1ccc(C2CCCCC2)c(Br)c1
Reactant: CCOC(=O)/C=C(\C)OCC
Solvent: CO
Product: CC(=O)/C=C(\C)c1ccc(C2CCCCC2)c(Br)c1
Yield: 69 %

Procedure:
(E)-4-(3-Bromo-4-cyclohexyl-phenyl)-3-pentene-2-one was prepared analogous to Example 52, from 3'-bromo-4'-cyclohexylacetophenone (b.p. 135°-138°C at 0.15 mm Hg; nD20 = 1.5740) an ethyl (E)-3-ethoxy-crotonate with a yield of 69% of theory. B.p. 170°-175°C at 0.3 mm Hg; m.p. 52°-53°C (from methanol).
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]1=[O:13].[C:14]1([CH3:23])[C:15]([N:20]=[C:21]=[O:22])=[CH:16][CH:17]=[CH:18][CH:19]=1>N1C=CC=CC=1>[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([NH:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]1=[O:13])=[O:22]
Reactant: Cc1ccccc1N=C=O
Reactant: Nn1c(=O)c(=O)[nH]c2ccccc21
Solvent: c1ccncc1
Product: Cc1ccccc1NC(=O)Nn1c(=O)c(=O)[nH]c2ccccc21
Temperature: 70 °C
Yield: 90.5 %

Procedure:
The procedure of Leeson, P. D. et al., J. Med. Chem 35: 1954-68 (1992) was adapted. A suspension of 1-amino-1,4-dihydro-2,3-quinoxalinedione (37 mg, 0.21 mMol) in pyridine (2.5 mL) was stirred at 70° C. until dissolving was completed. To the solution was then added o-tolyl isocyanate (27.8 mg, 0.21 mMol, Aldrich), which was stirred at 60° C. for 2 h, then overnight at room temperature. The solvent was evaporated under reduced pressure, the residue was washed by ether (2×2 mL) to give 59 mg of crude 1-[[(o-tolylamino)carbonyl]amino]-1,4-dihydro-2,3-quinoxalinedione (66% product; 30% tolyl-byproduct; 4% 1-amino-1,4-dihydro-2,3-quinoxalinedione by 1H NMR). Separated by chromatograph with silica gel (2 g) column, eluted with 100% benzene (20 mL) and benzene: acetone=1:1 (20 mL) and 100% acetone (20 mL) to remove most of impurity. The residue (43 mg of 1-[[(o-tolylamino)carbonyl]amino]-1,4-dihydro-2,3-quinoxalinedione) was washed with ethanol (2×2 mL) and ether (2×1 mL) to give 38 mg of pure 1-[[(o-tolylamino)carbonyl]amino]-1,4-dihydro-2,3-quinoxalinedione as a white powder (60%). Mp:decomposed from 265° C. IR (KBr, cm-1): 3375; 3237; 1718; 1693; 1675. NMR (1H, DMSO-d6) δ 2.161 (s, 3H); 6.996-7.380 (m, 8H); 8.530 (s, 1H), 9.343 (s, 1H); 12.155(s, 1H).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12.C[Mg]Br.C1COCC1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=[O:25])[CH:19]=1.O>C1COCC1>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([OH:25])[C:2]2[N:3]=[CH:4][N:5]3[CH:9]=[CH:8][S:7][C:6]=23)[CH:19]=1
Reactant: O=Cc1cccnc1
Reactant: Ic1ncn2ccsc12
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: OC(c1cccnc1)c1ncn2ccsc12
Reaction time: 0.33 h

Procedure:
A solution of 2.50 g of 7-iodoimidazo[5,1-b]thiazole in 50 ml of dry THF was cooled in ice, and 11.3 ml of a 0.93 M methylmagnesium bromide/THF solution was added to the cooled solution under an argon atmosphere. The mixture was stirred at that temperature for 20 min. Pyridine-3-aldehyde (1.04 ml) was then added thereto, and the mixture was stirred at that temperature for 40 min and then at room temperature for 4 hr. Water was added to the reaction solution, and the mixture was extracted five times with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and was then concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to give 1.925 g of 7-[(pyridin-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole.
Reaction SMILES: [OH-].[Ca+2].[OH-].[O:4]=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[P:18]([OH:22])([OH:21])([O-:20])=[O:19].[Na+:23]>>[OH-:4].[Na+:23].[P:18]([OH:22])([O-:21])([O-:20])=[O:19].[Na+:23].[Na+:23]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Reactant: O=P([O-])(O)O
Agent: [Ca+2]
Agent: [Na+]
Agent: [OH-]
Product: O=P([O-])([O-])O

Procedure:
To the above filtrate, a slurry containing 179 g of calcium hydroxide (32%) was added at a temperature of about 55 degrees C. An amount of 241 g of dicalcium phosphate was separated (49% humidity) leaving a solution of 1960 ml. The solution had a pH of 4.75 with a P2O5 concentration of 7.6%. This filtrate consisted substantially of pure monosodium phosphate; by its neutralization with a solution of 47.5% NaOH (containing 1.2% NaCl) to a pH of about 8.7, disodium phosphate was produced. In this neutralization operation, an appreciable amount of heat evolved, being accompanied by the precipitation of small particles of CaO and MgO in the form of hydroxyphosphate salts. After the removal of the fine precipitates, the filtrate was cooled to about 5 degrees, by a controlled cooling at the rate of about 10 degrees per hour. The chloride concentration in the mother-liquor was about 2% which gave rise to an increase of crystallization, the yield depending on NaCl concentration, known as salting out effect. An amount of 920 g of very pure crystals (14% humidity) of disodium phosphate were separated.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>ClCCl>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([F:24])=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][C@@H:3]([NH:2][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=2)[CH:22]=1
Reactant: O=C1CCC(=O)O1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)CCC(=O)O
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
A solution of (R)-ethyl 3-amino-4-(5′-chloro-2′-fluorobiphenyl-4-yl)butanoate hydrochloride (Intermediate 8-5: 293 mg, 0.777 mmol), succinic anhydride (93 mg, 0.932 mmol) and DIPEA (0.204 mL, 1.165 mmol) in dichloromethane (4 mL) is allowed to stir for 1.5 hours. The reaction is quenched with 1 M aqueous HCl and extracted with dichloromethane. The organic layer is separated and concentrated under reduced pressure. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-4-(1-(5′-chloro-2′-fluorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (294 mg). HPLC retention time=1.03 minutes (condition B); MS (m+1)=436.2; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.07 Hz, 3 H) 2.46-2.58 (m, 4 H) 2.64-2.68 (m, 2 H) 2.87 (A of ABX, Jab=13.64 Hz, Jax=7.83 Hz, 1 H) 2.99 (B of ABX, Jab=13.64 Hz, Jbx=6.57 Hz, 1 H) 4.11-4.22 (m, 2 H) 4.47-4.56 (m, 1 H) 6.60 (br d, J=8.59 Hz, 1 H) 7.05-7.10 (m, 1 H) 7.23-7.27 (m, 3 H) 7.39-7.41 (m, 1 H) 7:44-7.46 (m, 2 H).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH3:32].C(OCC)(=O)C>CN(C=O)C>[CH2:29]([N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCBr
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 95 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.350 g, 1.24 mmol), K2CO3 (0.427 g, 3.09 mmol), and 1-bromobutane (0.178 g, 1.30 mmol) in DMF (6.2 mL). Heat at 95° C. for 5.5 hours, then at 50° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 20% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 340.2 (M+H)+, HRMS calcd for C20H26N3O2 340.2025 (M+H)+, found 340.2019, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min. 20-95% over 18 min], tR=9.6 min, 98.3% purity.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:13]1[CH2:18][CH2:17][CH2:16][N:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N:15]1([C:2]2[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:16][CH2:17][CH2:18][N:13]=[CH:14]1
Reactant: Cc1cc(F)cc(N)c1[N+](=O)[O-]
Reactant: C1=NCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(N2C=NCCC2)cc(N)c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 67.2 %

Procedure:
To a stirred solution of 2.0 g (11.76 mmol) of the 5-Flouro-3-methyl-2-nitro aniline in 10 mL of DMSO was added 1.2 g (14.11 mmol) of 1,4,5,6-Tetrahydropyrimidine, and 2.43 g (17.64 mmol) of potassium carbonate, and the mixture was heated at 100° C. for 10 hrs, cooled, diluted with water, and extracted with Ethylacetate containing 5% methanol. The combined organic extract was washed with water, brine and dried (Na2SO4). Evaporation of the solvent furnished the residue, which was chromatographed (20% of 2M ammonia in methanol and dichloromethane) to produce 1.85 g (67%) of the product as red solid. 1H NMR (400 MHz, CD3OD) δ 7.89 (1H,s), 6.53 (1H,d, J=2.57 Hz), 6.44 ((1H, d, J=2.1 Hz), 7.04 (1H, d, J=2.1 Hz), 3.70 (2H, t, J=6.0 Hz), 3.41 (2H, t, J=5.65 Hz, 2.43 (3H, s), 2.05 (2H, m) LCMS (M+H)+ m/z 235 (t=0.78 min).
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[C:9]([C:12]1[S:13][C:14]([Br:17])=[CH:15][CH:16]=1)(=[O:11])[CH3:10].Cl>C1COCC1.O>[Br:17][C:14]1[S:13][C:12]([C:9](=[O:11])[CH2:10][C:3]([O:6][CH3:7])=[O:8])=[CH:16][CH:15]=1
Reactant: COC(=O)OC
Reactant: CC(=O)c1ccc(Br)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC(=O)c1ccc(Br)s1
Yield: 99 %

Procedure:
Sodium hydride (1.95 g of 60% dispersion in oil, 0.045 mol), dimethyl carbonate (50 mL) and THF (40 mL) were added to a flame dried flask equipped with stirrer and dropping funnel. 2-Acetyl-5-bromothiophene (5.0 g, 0.024 mol) in 20 mL THF was added dropwise. The mixture was then heated at reflux for 2 hours, then poured into 250 mL of water, acidified to pH 2.0 with lN HCl and extracted 3×200 mL ether. The organic layers were combined, dried (MgSO4) and stripped to yield 6.4 g (99%) of present title product as an oil; tlc Rf 0.42 (CHCl3).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[SH:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:25]>CN(C=O)C.C(OCC)(=O)C>[CH2:33]([CH:28]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27][O:26][C:24](=[O:25])[CH2:23][CH2:22][S:21][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:34]
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC(CC)COC(=O)CCSc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a suspension of methyl 4-fluoro-3-nitrobenzoate (10.0 g, 50.2 mmol) and potassium carbonate (13.9 g, 100 mmol) in DMF (120 mL) was added dropwise under ice-cooling 2-ethylhexyl 3-sulfanylpropanoate (12.1 g, 55.2 mmol), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. This solution was applied to basic silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 3:1) to give the title compound (20.0 g, quantitative).
Reaction SMILES: [C:1](Cl)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[CH2:9]([NH:11][NH:12][C:13]([NH2:15])=[S:14])[CH3:10]>CC(C)=O>[CH2:9]([N:11]([C:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2])[NH:12][C:13]([NH2:15])=[S:14])[CH3:10]
Reactant: CCNNC(N)=S
Reactant: CCOC(=O)C(=O)Cl
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)N(CC)NC(N)=S
Reaction time: 1 h

Procedure:
Ethoxalyl chloride (10.6 cc) is added dropwise, in the course of 10 minutes, to a solution, at 20° C., of 1-ethyl-thiosemicarbazide (11.9 g) in acetone (200 cc). The temperature rises to 43° C., the mixture is stirred for 1 hour without heating and is concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa), the residue is taken up in methanol (30 cc) and the crystallisation is started. After filtration and drying, 1-ethyl-1-ethoxalyl-thiosemicarbazide (13.2 g) is obtained in the form of a white solid melting at 170° C.
Reaction SMILES: [Na].CC(S)(C)C.C[S:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.Cl>CN(C)C=O>[SH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1
Reactant: CSc1ccc(C=O)cc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)(C)S
Solvent: CN(C)C=O
Product: O=Cc1ccc(S)cc1
Temperature: 25 °C
Yield: 38.4 %

Procedure:
Combine 2-methyl-2-propanethiol sodium salt (2.9 g, 26.3 mmol) and 4-(methylthio)benzaldehyde (2.0 g, 13.2 mmol) with dimehtylformamide (40 mL) in a dry flask then heat at 160° C. for 4 hours. Cooled to room temperature, poured into 3N aqueous hydrochloric acid (400 mL) then extracted with dichloromethane (3×75 mL). The combined dichloromethane extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (3 g). The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate and hexanes to yield 4-mercapto-benzaldehyde (0.7 g): 1H NMR (DMSO-D6, 300.00 MHz): 9.9 (s, 1H), 7.7 (d, 2H), 7.5 (d, 2H). Step 2 6-(4-Formyl-phenylsulfanyl)-nicotinamide
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3](O)[OH:4].[NH:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11]>C(Cl)(Cl)Cl>[Cl:1][C:2]([Cl:7])([Cl:6])[C@@H:3]1[N:8]2[CH2:15][CH2:14][CH2:13][C@H:9]2[C:10](=[O:11])[O:4]1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: ClC(Cl)Cl
Product: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Yield: 72 %

Procedure:
Chloral hydrate (1.5 eq) was added to a solution of L-proline in CHCl3 (1 M), the suspension was refluxed (inverse Dean-Stark trap) for 6 h; the mixture was washed with water and the aq. phase re-extracted with CHCl3, the combined organic layers were dried and concentrated. Recrystallization (EtOH) of the residue afforded (3R,7aS)-3-(trichloromethyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-1-one in 72% yield. This material was dissolved in dry THF (0.12M), 2M LDA (1.5 eq) was added at −78° C. and the mixture was stirred for 40 min; 60% benzyl chloromethyl ether (3 eq) was added and stirring was continued from −78 to 0° C. for 3 h; after quenching with water the mixture was extracted with CHCl3 (3×), dried over Na2SO4 and concentrated. Flash chromatography (PE:EtOAc 5:1) afforded the title compound which was used without further characterisation in the next reaction (48%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]([C:11]1[N:12]=[CH:13][NH:14][CH:15]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:9][C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=Cc1c[nH]cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Fc1ccc(NCc2c[nH]cn2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 15.5 %

Procedure:
To a solution of 4-fluoroaniline (0.60 g, 5.40 mmol) in 1,2-dichloroethane (5 ml) were added 4-formylimidazole (0.78 g, 8.10 mmol), sodium triacetoxyborohydride (2.29 g, 10.8 mmol) and acetic acid (0.06 ml). The reaction mixture was stirred at 50° C. for 4 h. The reaction mixture was then concentrated in vacuo and the residue was purified using flash chromatography (column: Isolute® Flash-NH2 (Separtis); eluent: methanol/dichloromethane gradient) to yield a white solid (160 mg, 16%); MS (ISP): 192.2 ((M+H)+.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]3[N:17]([CH:18]([CH3:20])[CH3:19])[N:16]=[CH:15][N:14]=3)[N:12]=2)=[C:4](F)[CH:3]=1.C1(=O)O[CH2:25][CH2:24][O:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[N:9]([CH:10]=[C:11]([C:13]4[N:17]([CH:18]([CH3:20])[CH3:19])[N:16]=[CH:15][N:14]=4)[N:12]=3)[CH2:25][CH2:24][O:23][C:4]=2[CH:3]=1
Reactant: O=C1OCCO1
Reactant: CC(C)n1ncnc1-c1c[nH]c(-c2ccc(Br)cc2F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 100 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
A solution of 5-[2-(4-bromo-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-1H-[1,2,4]triazole (10.0 g, 28.6 mmol) in DMF (100 mL) was treated with ethylene carbonate (5.3 g, 60.1 mmol) and cesium carbonate (13.9 g, 42.5 mmol) and then heated at 100° C. for 72 h. Further cesium carbonate (9.0 g, 27.5 mmol) and water (0.5 mL) were added and heating continued for 24 h before concentrating the reaction mixture in vacuo. The resultant residue was partitioned between DCM and water, the organic layer was isolated, washed with water then brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, 1% MeOH in DCM) to give 194 as an off-white solid (5.78 g, 58%). 1H NMR δ (ppm) (CDCl3): 8.04 (1H, s), 7.83 (1H, s), 7.50-7.38 (3H, m), 5.93-5.84 (1H, m), 4.07-4.02 (2H, m), 3.93-3.88 (2H, m), 1.53-1.46 (6H, m)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)[CH:2]=1.[CH3:14][NH:15][CH3:16].Cl.C([BH3-])#N.[Na+]>CO.O1CCOCC1>[CH3:14][N:15]([CH3:16])[CH2:12][C:10]1[S:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:8][CH:9]=1
Reactant: CNC
Reactant: O=Cc1ccc(-c2cccnc2)s1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)Cc1ccc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.4 %

Procedure:
To a solution of 13 (90 mg, 0.48 mmol) was added a solution of dimethylamine (2.9 M, 0.99 mL, 2.85 mmol) in anhydrous CH3OH, a solution of HCl (4.0 M, 0.24 mL, 0.95 mmol) in anhydrous 1,4-dioxane and sodium cyanoborohydride (30 mg, 0.48 mmol). The flask was purged with argon and stirred under an atmosphere of argon at room temperature for 24 h. The solution was adjusted to pH 2 with conc. HCl and the solvent was removed in vacuo. The residue was dissolved in water, washed with Et2O (3×10 mL), adjusted to pH 10 with NaOH(aq) (10 N), extracted with Et2O (3×20 mL), dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CHCl3, 2.5/97.5, Rf=0.15) to afford the title compound 42 (57 mg, 55% yield) as a yellow oil: 1H NMR (CDCl3) δ 8.85 (br s, 1H), 8.48 (m, 1H), 7.82 (m, 1H), 7.28 (m, 1H), 7.21 (d, J=3.7 Hz, 1H), 6.91 (d, J=3.5 Hz, 1H), 3.65 (s, 2H) 2.31 (s, 6H); LRMS (ESI) m/z calcd for C12H15N2S [M+H]+ 219. found 219; m/z calcd for C10H8NS [M−N(CH3)2]+ 174. found 174; HRMS (ESI) m/z calcd for C12H15N2S [M+H]+ 219.0956. found 219.0955; HPLC>99% (tR=8.90 min, 55 (A):45 (B): 0.009 (C); tR=6.28 min, 55 (A):45 (B): 0.018 (C)).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:15][CH2:14][C:13]2[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:11]3[CH:10]=[CH:9][C:8]([C:24]#[N:25])=[CH:7][C:6]=3[C:5]=2[CH2:4]1.C(N(CC)CC)C.[CH:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1>ClCCl>[C:24]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:13]1[CH2:14][CH2:15][CH:3]([NH:2][S:36]([CH:33]3[CH2:35][CH2:34]3)(=[O:38])=[O:37])[CH2:4][C:5]2=1)#[N:25]
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(N)C1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(NS(=O)(=O)C2CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
Combine 6-amino-9-(3-fluoro-benzyl)6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile, hydrochloride salt (Preparation 54) (125 mg, 0.35 mmol) and triethylamine (0.195 mL, 1.4 mmol) in dichloromethane (3 mL) under nitrogen. Add cyclopropylsulfonylchloride (51 mg, 0.36 mmol) in dichloromethane (1 mL). Stir for 18 h at room temperature. Purify the reaction solution directly by flash chromatography, eluting with 20% ethyl acetate/hexane and then a gradient up to 50% ethyl acetateihexane to obtain 80 mg. Triturate in diethyl ether to obtain 61 mg (41%) of a tan solid. MS (ES): m/z 424 (M+1), 422 (M−1); 1H NMR(DMSO-d6): δ 7.98 (d, 1H, J=1.3 Hz), 7.56 (d, 1H, J=8.4 Hz), 7.41 (dd, 1H, J=8.4, 1.3 Hz), 7.36-7.30 (m, 2H), 7.07 (dt, 1H, J=8.7, 2.5 Hz), 6.88 (d, 1H, J=9.7 Hz), 6.83 (d, 1H, J=7.9 Hz), 5.42 (d, 2H, J=5.3 Hz), 3.68 (m, 1H), 3.10 (dd, 1H, J=15.4, 5.3 Hz), 2.90-2.81 (m, 1H), 2.79-2.61 (m, 3H), 2.13 (m, 1H), 1.86 (m, 1H), 0.98-0.91 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13]Br)[CH:8]=1.[C-:20]#[N:21].[Na+].CC(C)=O>C(O)C>[Br:1][C:2]1[O:3][C:4]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:20]#[N:21])[CH:8]=1
Reactant: [C-]#N
Reactant: Clc1ccc2oc(Br)c(-c3cccc(CBr)c3)c2c1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: N#CCc1cccc(-c2c(Br)oc3ccc(Cl)cc23)c1

Procedure:
The product of Step D, 2-bromo-3-(3-bromomethylphenyl)-5-chlorobenzofuran is reacted with sodium cyanide by heating to reflux in a solvent mixture of acetone and ethanol. Evaporation provides the desired product, 2-bromo-5-chloro-3-(3-cyanomethylphenyl)benzofuran.