Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1.[CH3:15][N:16]([CH:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25])[CH3:17].[Cl-:32].[NH4+]>CCOCC>[ClH:32].[CH3:17][N:16]([CH:18]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1([CH2:9][C:8]1[CH:11]=[CH:12][C:5]([O:4][C:3]([F:14])([F:13])[F:2])=[CH:6][CH:7]=1)[OH:25])[CH3:15]
Reactant: [Cl-]
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1ccccc1)C1CCCCC1(O)Cc1ccc(OC(F)(F)F)cc1
Product: Cl
Temperature: 25 °C
Yield: 41.7 %

Procedure:
0.10 g (4.2 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 1.0 g (4.2 mmole) of 4-(trifluoromethoxy)benzyl bromide dissolved in 10 ml of ether was added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 0.8 g (3.5 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 was dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 30 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 1.65 g of crude base (121% of theory) were obtained. 0.64 g of 2-(dimethylaminophenylmethyl)-1-(4-trifluoromethoxybenzyl)cyclohexanol, hydrochloride (41.7% of theory) were obtained from the crude base according to the procedure described in Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 178° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:18]1[N:23]=[CH:22][C:21]([C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:20][N:19]=1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:18]1[N:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:22][N:23]=1
Reactant: CCCCCCCC#Cc1cnc(-c2ccc(OCCCCCCCC)c(F)c2F)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCc1cnc(-c2ccc(OCCCCCCCC)c(F)c2F)nc1
Yield: 91.8 %

Procedure:
-The nonynylpyrimidine 38 (1.50 g, 3.39 mmol) was hydrogenated over 5% Pd/C in ethyl acetate to give the nonylpyrimidine 39 (1.39 g, 92%) (from MeOH/EtOH), transitions/° C. K 42.8 SC 53.6 I; νmax /cm-1 (KBr) 2920, 2950, 1625, 1540, 1475, 1465, 1430, 1310, 1200 and 1080s; δ 0.90 (6 H, m, Me x 2), 1.16-1.56 (22 H, m), 1.67 (2 H, quint, ArCH2CH2), 1.85 (2 H, quint, OCH2CH2), 2.63 (2 H, t, ArCH2), 4.10 (2 H, t, OCH2), 6.82 (1 H, ddd, J 8.5, 8 and 2, 5'-H), 7.80 (1 H, ddd, J 8.5, 8 and 2, 6'-H) and 8.65 (2 H, s, 4- and 6-H); m/z 446 (M+), 334, 305, 277, 263, 249, 235 and 222.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]2[CH:18]=[C:19]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[CH:20]=[N:21][CH:22]=2)=[CH:12][CH:11]=3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.S(Cl)(Cl)(=O)=O.[CH3:45][CH:46]([CH3:52])[CH2:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[CH3:45][CH:46]([CH3:52])[CH2:47][S:48]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]2[CH:18]=[C:19]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[CH:20]=[N:21][CH:22]=2)=[CH:12][CH:11]=3)[CH2:2][CH2:3]1)(=[O:50])=[O:49]
Reactant: O=S(=O)(Nc1cncc(-c2ccc3ncc(N4CCNCC4)nc3c2)c1)c1ccccc1
Reactant: CC(C)CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)CS(=O)(=O)N1CCN(c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.4 %

Procedure:
To a solution of N-{5-[3-(1-piperazinyl)-6-quinoxalinyl]-3-pyridinyl}benzenesulfonamide (0.20 mmol) and triethylamine (0.20 mmol) in dichloromethane (2 ml) was added a sulfonyl chloride such as 2-methyl-1-propanesulfonyl chloride (0.22 mmol). The reaction stirred for 18 hours at ambient temperature and purified on silica by column chromatography (80% ethyl acetate/hexanes). The desired fractions were combined and concentrated to give the title compound (22 mg, 20%) as an off-white solid. MS(ES)+ m/e 567.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]2)[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH2:23][C:24]([NH2:26])=[NH:25].O>CO>[NH2:25][C:24]([NH2:26])=[N:23][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]2)=[CH:11][C:2]=1[CH3:1]
Reactant: N=C(N)N
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(N2CCCC(O)C2)cc1C
Solvent: O
Solvent: CO
Product: Cc1cc(N2CCCC(O)C2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Reaction time: 1 h

Procedure:
A solution of 4.2 g of methyl 2-methyl-4-(3-hydroxy-1-piperidyl)-5-methylsulfonylbenzoate [obtainable by reacting 3-hydroxypiperidine with 2-methyl-4-chloro-5-methylsulfonylbenzoic acid followed by esterification] and 3.89 g of guanidine in 20 ml of methanol is stirred at 50° over a period of three hours. The solution is cooled, water is added, the mixture is stirred for 1 hour and the precipitate which is formed is separated off. After recrystallization from acetone/methanol, N-diaminomethylene-2-methyl-4-(3-hydroxy-1-piperidyl)-5-methylsulfonylbenzamide is obtained, m.p. 194-196°.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH:6]1[C:13](=[O:14])[CH2:12][C:10](=O)[NH:9][C:7]1=[O:8]>O>[Cl:3][N:6]1[C:13](=[O:14])[CH:12]=[CH:10][NH:9][C:7]1=[O:8]
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=c1cc[nH]c(=O)n1Cl

Procedure:
Phosphoryl chloride (55 ml) is carefully added to barbituric acid (10 g, 78.1 mmol) at 0° C. Water (1.7 ml) is then added dropwise such that the temperature does not exceed 5° C. The mixture is boiled under reflux for 5 h and, after it has cooled down, poured onto ice. The product is extracted with ethyl acetate (3×100 ml) and dried (Na2 SO4). The mixture is filtered and the solvent is distilled off in vacuo.
Reaction SMILES: ClC(O[CH2:5][CH:6](C)C)=O.[C:9]([O:13][C:14]([NH:16][CH2:17][P:18]([CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:20])[OH:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O)C.C(N(CC)CC)C>C(Cl)Cl>[C:9]([O:13][C:14]([NH:16][CH2:17][P:18]([CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:19])[O:20][CH2:5][CH3:6])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCP(=O)(O)CNC(=O)OC(C)(C)C
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: CCOP(=O)(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C
Yield: 20.1 %

Procedure:
Isobutyl chloroformate (1.50 ml; 11.48 mmol) is added dropwise and with stirring to a solution of the phosphinic acid 1 (3.200 g; 9.88 mmol) in a mixture of methylene chloride (50 ml), ethanol (3.00 ml; 51.59 mmol), triethylamine (1.40 ml; 10.06 mmol) and N,N-dimethylaminopyridine (10 mg) at 0° C. After 90 minutes the reaction solution is extracted with saturated aqueous ammonium chloride solution (30 ml) and saturated aqueous KHCO3 solution (30 ml). The organic phase is dried over Na2SO4 and evaporated under reduced pressure. The phosphinate 2 (700 mg, 20% of theory) is obtained after purification on silica gel, using column chromatography (ethyl acetate/heptane=3/2). Spectroscopic data is given above.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=O.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:44][C:45]1[CH:61]=[CH:60][C:48]([O:49][CH2:50][CH2:51][NH:52]C(=O)OC(C)(C)C)=[C:47]([C:62]2[N:66]([CH3:67])[N:65]=[CH:64][CH:63]=2)[CH:46]=1.Cl.CCOCC>ClCCl>[NH2:52][CH2:51][CH2:50][O:49][C:48]1[CH:60]=[CH:61][C:45]([NH:44][C:3](=[O:5])[C:2](=[O:1])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)=[CH:46][C:47]=1[C:62]1[N:66]([CH3:67])[N:65]=[CH:64][CH:63]=1
Reactant: Cc1ccc(C(=O)C(=O)O)cc1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32.2 %

Procedure:
The 2-oxo-2-p-tolylacetic acid (14.82 mg, 1.2 eq),), triethylamine (31.45 μL, 3.0 eq) and HATU (34.32 mg, 1.2 eq) were dissolved in 1 mL of dichloromethane and stirred at room temperature for 20 minutes. At this time tert-butyl 2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (25.0 mg, 75.2 μmol) dissolved in 0.5 mL of dichloromethane was added and the reaction was stirred at room temperature for 18 hr. The solvent was evaporated under a stream of nitrogen and the residue was dissolved in 0.5 mL of ethyl acetate. To this was added 2.0M hydrochloric acid in ether (188 μL, 5 eq) and the reaction was stirred at room temperature overnight. The solvent was evaporated under a stream of nitrogen and the residue was dissolved in 1 mL of dimethylsulfoxide and purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 32.2% yield. LCMS m/z (%)=379 (M+H, 100. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3H), 3.12-3.21 (m, 2H), 3.71 (s, 3H), 4.19 (t, J=5.56 Hz, 2H), 6.37 (d, J=1.52 Hz, 1H), 7.26 (d, J=9.09 Hz, 1H), 7.42 (d, J=8.59 Hz, 2H), 7.49 (d, J=2.02 Hz, 1H), 7.70 (d, J=2.53 Hz, 1H), 7.82 (dd, J=9.09, 2.53 Hz, 1H), 7.97 (d, J=8.08 Hz, 2H), 10.96 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:14]([O-])=O.[H][H]>CO.[C].[Pd]>[ClH:1].[NH2:14][C:3]1[CH:4]=[C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:7][CH:2]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C(=O)O)c1cccc(N)c1
Product: Cl
Yield: 99.9 %

Procedure:
In 50 ml of methanol was dissolved 10.0 g of 2-(4-chloro-3-nitrophenyl)-2-methylpropionic acid. To the resulting mixture was added 1.0 g of 10% palladium carbon. In a hydrogen gas atmosphere, the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 8.84 g of the title compound.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].S1(CCCC1)(=O)=[O:6]>>[CH2:1]=[CH:2][CH:3]([OH:6])[CH3:4].[CH2:1]([OH:6])[CH:2]=[CH:3][CH3:4]
Reactant: O=S1(=O)CCCC1
Reactant: C=CC=C
Product: C=CC(C)O
Product: CC=CCO
Temperature: 100 °C
Reaction time: 6 h
Yield: 26 %
Yield: 60 %

Procedure:
In accordance with Example 1, a homogeneous solution of 6.2 grams (0.11 moles) of butadiene and 100 milliliters of a 65 volume percent aqueous sulfolane solution were reacted in the presence of a cation exchanger sold under the trademark Lewatit SPC 118 at a temperature of 100° C. After agitating at 100° C. for 6 hours, 76 percent of the mixture had reacted. A yield of 60 percent 1-butene-3-ol and a yield of 26 percent 2-butene-1-ol (crotylalcohol) was obtained.
Reaction SMILES: CN=C=O.[C:5]1([C:11]2[C:19]([CH:20]=[N:21]O)=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[C:5]1([C:11]2[C:19]([C:20]#[N:21])=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: ON=Cc1c(-c2ccccc2)nn2ccccc12
Agent: CN=C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: N#Cc1c(-c2ccccc2)nn2ccccc12
Reaction time: 8 h
Yield: 43.7 %

Procedure:
A solution of methyl isocyanate (0.19 g) in methylene chloride (2, ml) was added dropwise to a mixture of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde oxime (0.52 g) in chloroform (4 ml) with stirring and ice-cooling. The mixture was stirred at room temperature for 2 hours and allowed to stand at room temperature overnight. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel (20 g) with methylene chloride as an eluent. The fractions containing the object compound were combined (20 ml) and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 2-phenylpyrazolo[1,5-a]pyridine-3-carbonitrile (0.21 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[C:26]([CH3:34])=[CH:27][C:28]([Cl:33])=[C:29]([CH:32]=3)[C:30]#[N:31])[C@@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl.N1C=CC=CC=1>[Si:17]([O:16][C@@H:14]([CH3:15])[C@H:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:37])[CH3:36])=[CH:7][CH:6]=2)=[N:9][N:10]=1)[NH:24][C:25]1[CH:32]=[C:29]([C:30]#[N:31])[C:28]([Cl:33])=[CH:27][C:26]=1[CH3:34])([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Cc1cc(Cl)c(C#N)cc1N[C@@H](c1nnc(-c2ccc(N)cc2)o1)[C@H](C)O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2nnc([C@H](Nc3cc(C#N)c(Cl)cc3C)[C@H](C)O[Si](C)(C)C(C)(C)C)o2)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a pre-cooled (0° C.) solution of 5-((1R,2S)-1-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-(tert-butyldimethylsilyloxy)propylamino)-2-chloro-4-methylbenzonitrile (intermediate 77d) (200 mg, 0.40 mmol) in CH2Cl2 (4.0 mL) and pyridine (1.04 mL) was added, portion wise, acetyl chloride (0.14 mL, 2.0 mmol). Upon complete addition the reaction mixture was warmed slowly to room temperature and stirred for 23 h. The reaction mixture was then cooled to 0° C. and quenched with 10% ap HCl (5 mL) then H2O (15 mL) was added. The solution was extracted with CH2Cl2 (2×30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide an orange oil, which was used without further purification (199 mg, 92%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.11 (d, J=8.4 Hz, 2 H), 7.87 (d, J=8.6 Hz, 2 H), 7.80 (br s, 1 H), 7.54 (d, J=8.4 Hz, 1 H), 7.67 (d, J=8.4 Hz, 1 H), 5.57 (d, J=8.9 Hz, 1 H), 4.99 (dd, J=1.8, 8.9 Hz, 1 H), 4.76-4.68 (m, 1 H), 2.58 (s, 3 H), 2.44 (s, 3 H), 1.62 (d, J=6.3 Hz, 3 H), 1.07 (s, 9 H), 0.27 (s, 3 H), 0.00 (s, 3 H).
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])OC(C)(C)C)[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:17](=[O:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:50][C:51]1[CH:60]=[C:59]2[C:54]([C:55]([N:62]3[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]3)=[CH:56][C:57]([NH2:61])=[N:58]2)=[CH:53][CH:52]=1>>[NH2:61][C:57]1[CH:56]=[C:55]([N:62]2[CH2:63][CH2:64][N:65]([C:10]([NH:9][C@H:8]3[CH2:7][CH2:6][CH2:5][CH2:4][N:3]([C:17](=[O:25])[CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:2]3=[O:1])=[O:16])[CH2:66][CH2:67]2)[C:54]2[C:59](=[CH:60][C:51]([Cl:50])=[CH:52][CH:53]=2)[N:58]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCN(C(=O)Cc2ccccc2)C1=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(C(=O)Cc4ccccc4)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 213, [(3S)-hexahydro-2-oxo-1-(phenylacetyl)-1H-azepin-3-yl]-carbamic acid, 1,1-dimethylethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 535 (M++1). 1H NMR (CDCl3, 400 MHz): δ 1.20˜1.50 (m, 2H), 1.80˜2.20 (m, 4H), 3.10˜3.20 (m, 5H), 3.60˜3.70 (m, 4H), 4.28 (AB, 2H), 4.75 (dd, 1H), 4.80˜4.95 (m, 3H), 5.85 (d, 1H), 6.16 (s, 1H), 7.18 (dd, 1H), 7.22˜7.36 (m, 5H), 7.62 (d, 1H), 7.72 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[O:13])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:14][Mg]Br.C(OCC)(=O)C.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([OH:13])[CH3:14])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=Cc1cc(Br)cc(C(=O)O)c1O
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)c1cc(Br)cc(C(=O)O)c1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.0 g (4.1 mmol) of 5-bromo-3-formyl-2-hydroxy-benzoic acid was dissolved in 100 mL of anhydrous THF under nitrogen. The solution was cooled in an ice-bath and 13.6 ml of a 3 M solution of methyl magnesium bromide was added. The mixture was stirred for 16 h, slowly warming to room temperature. The resulting solution was distributed between ethyl acetate and dilute aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate and evaporated to afford 1.09 g of 5-bromo-2-hydroxy-3-(1-hydroxy-ethyl)-benzoic acid as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 7.76 (d, 1H), 7.72 (d, 1H), 4.98 (q, 1H), 1.30 (d, 3H), MS: m/z 258.9+261.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[N:4]([NH2:19])[CH:3]=1.CN1CCCC1=O.Cl.Cl[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1[F:35].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:35][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][C:29]=1[NH:19][N:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:7][CH:6]=2)[C:2]([CH3:1])=[CH:3]1
Reactant: Cc1cn(N)c2ccc(OCc3ccccc3)cc12
Reactant: Fc1cnccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cn(Nc2ccncc2F)c2ccc(OCc3ccccc3)cc12
Temperature: 80 °C
Yield: 60.5 %

Procedure:
To a solution consisting of 3-methyl-5-(phenylmethoxy)-1H-indol-1-amine (4.81 g) and 1-methyl-2-pyrrolidinone (83 ml) was added 4-chloro-3-fluoro pyridine hydrochloride (3.20 g). The resulting mixture was heated at 80° C. for 2 hours. Upon cooling to room temperature, dilute aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted with EtOAc (3x). The combined organic layers were washed successively with water (2x) and brine (1x), and thereafter dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 50% ethyl acetate/dichloromethane) afforded 4.0 g of the desired product as a solid, m.p. 210°-213° C.
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:5]=[C:6]2[NH:12][C:11](=[O:13])[C:10]3([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)[C:7]2=[N:8][CH:9]=1.[Cl-].[NH4+]>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]2[NH:12][C:11](=[O:13])[C:10]3([CH2:18][CH2:17][C:16]([OH:19])([CH3:1])[CH2:15][CH2:14]3)[C:7]2=[N:8][CH:9]=1
Reactant: O=C1CCC2(CC1)C(=O)Nc1cc(Br)cnc12
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCC2(CC1)C(=O)Nc1cc(Br)cnc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyllithium (1.6 M in diethyl ether, 4.88 mL, 7.81 mmol) was added dropwise to a stirred solution of 6′-bromospiro[cyclohexane-1,3′-pyrrolo[3,2-b]pyridine]-2′,4(1′H)-dione (preparation 18, 1.00 g, 3.39 mmol) in tetrahydrofuran (30 mL) at −78° C. The mixture was warmed to 0° C. over 3 h and stirred overnight at ambient temperature. Additional methyllithium (1.6 M in diethyl ether, 4.24 mL, 6.78 mmol) was added dropwise at −78° C. and the mixture was warmed to ambient temperature stirred overnight at ambient temperature. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (0.1% Et3N in 1:1 to 3:1 ethyl acetate/hexanes) gave the two pure isomers of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)cn1
Yield: 100 %

Procedure:
A mixture of 2-fluoro-5-methyl-pyridine (15.00 mL, 135 mmol), N-bromosuccinimide (24.03 g, 135 mmol) and benzoyl peroxide (1.635 g, 6.75 mmol) in carbon tetrachloride (100 mL) was heated at reflux for 2.5 h. The mixture was cooled and filtered through a medium-fritted funnel The solid was rinsed with DCM (3×50 ml). The filtrate was concentrated to give 5-(bromomethyl)-2-fluoropyridine (25.7 g, 135 mmol, 100% yield) as an orange oil. m/z (ESI, +ve ion) 191.9 (M+H)+. The mixture was immediately carried into the next step of the synthesis without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH:15]=[N:14][C:13]([C:16]([O:18]C)=[O:17])=[N:12]1.ClC1C=C(N2C=NC(C(O)=O)=N2)C=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[N:14][C:13]([C:16]([OH:18])=[O:17])=[N:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc[nH]n1
Reactant: OB(O)c1cccc(F)c1
Agent: O=C(O)c1ncn(-c2cccc(Cl)c2)n1
Product: O=C(O)c1ncn(-c2cccc(F)c2)n1

Procedure:
This intermediate was prepared from 3-fluorophenylboronic acid and methyl 1,2,4-triazole-3-carboxylate in two steps according to the preparation of 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:16](/[CH:17]=[CH:12]/[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2ccc(Cl)cc2n1
Reactant: O=Cc1cccc(O)c1
Product: CC(=O)Oc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1

Procedure:
A solution of 7-chloroquinaldine (10 g, 56.3 mmol) and 3-hydroxybenzaldehyde (6.87 g, 56.3 mmol) in 25 ml of acetic anhydride is heated at 130° C. for 16 hours. The reaction mixture is concentrated and the beige solid recrystallized from hexane-ethyl acetate to afford (E)-3-(7-chloro-2-quinolinylethenyl)phenyl acetate which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].S(Cl)([Cl:15])(=O)=O>C(Cl)(Cl)Cl>[Cl:11][C:2]([Cl:1])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[C:8]([Cl:15])[CH:9]=1)=[O:4]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(Cl)c[nH]1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 107.4 %

Procedure:
To a solution of 2-(trichloroacetyl)pyrrole (4.0 g, 18.83 mmol) in chloroform (28 ml) at 0° C. was added sulfuryl chloride (13 mL, 13.2 mmol). The mixture was stirred for 17 hours at room temperature. TLC analysis indicated 50% conversion of starting material. Sulfuryl chloride (13 mL, 13.2 mmol) was added and the reaction mixture was stirred for another 4 hours at room temperature. The reaction was quenched with distilled water (50 mL). CH2Cl2 (50 mL) was added to the reaction and the solution was transferred to a separatory funnel and the organic layer was isolated while the aqueous layer was back extracted with CH2Cl2 (2×50 mL). The combined organic layers were collected, dried (MgSO4), filtered, and concentrated in vacuo to yield 3.5 g of the above compound (14.18 mmol, yield 75%). 1H-NMR (CDCl3-d1) δ 9.45 (s, 1H), 7.27 (dd, J=2.8, 1.6, 1H), 7.12 (dd, J=3.2, 1.6 Hz, 1H).