Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][C:19](=[O:25])[NH:20]2.N1CCCCC1>C(O)C>[CH3:14][C:7]1[NH:8][C:9]([CH:12]=[C:18]2[C:17]3[C:21](=[CH:22][CH:23]=[CH:24][C:16]=3[CH3:15])[NH:20][C:19]2=[O:25])=[C:10]([CH3:11])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cccc2c1C(=Cc1[nH]c(C)c(CCC(=O)O)c1C)C(=O)N2
Yield: 37 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.5 mg), 74 mg 4-methyl-2-oxindole, and 75 μL piperidine in 3 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N of aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 60 mg (37%) of the title compound as a green solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:13]=[O:14])=O)(C)(C)C.[CH:15]1([Mg]Cl)[CH2:17][CH2:16]1.C(=O)([O-])O.[Na+].ClCCl>O1CCCC1>[CH:15]1([C@H:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[OH:14])[CH2:17][CH2:16]1
Reactant: Cl[Mg]C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O[C@H](C1CC1)C1CCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a solution of (R)-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 1 mmol) in tetrahydrofuran at −78° C. was added a 1 M solution of cyclopropylmagnesium chloride (1.3 ml, 1.3 mmol). After stirring for 1 h at room temperature and addition of aqueous sodium hydrogencarbonate, extraction (3 times with dichloromethane), drying of the combined organic layers over sodium sulfate and evaporation of the solvents the crude product was heated with aqueous sodium hydroxide at 100° C. for 3 days to give 20 mg of crude cyclopropyl-(R)-pyrrolidin-2-yl-methanol which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:14]4[O:22][CH:21]=[CH:20][C:15]=4[CH:16]=[N:17][C:18]=3[NH2:19])=[N:9][N:10]=2)[N:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:23]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][O:12][C:13]4[C:14]5[O:22][CH:21]=[CH:20][C:15]=5[CH:16]=[N:17][C:18]=4[NH2:19])=[N:9][N:10]=3)[N:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ncc2ccoc2c1OCc1nnc2ccc(Cl)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc2ccoc2c1OCc1nnc2ccc(-c3ccccc3)nn12

Procedure:
A mixture of 7-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethoxy]furo[3,2-c]pyridine-6-ylamine (15.0 mg, 0.047 mmol), phenylboronic acid (11.5 mg, 0.095 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), potassium carbonate (19.6 mg, 0.142 mmol) and 4:1 dioxane:water (2 mL) was heated in a microwave reactor at 100° C. for 30 min. The solution was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=5.94 (s, 2H), 6.78 (d, J=2.3 Hz, 1H), 7.52-7.60 (m, 4H), 7.94-8.00 (m, 4H), 8.32 (d, J=9.6 Hz, 1H). MS (ES+): m/z 359.04 (100) [MH+]. HPLC: tR=2.21 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[CH3:5][P:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1>C1(C)C=CC=CC=1>[Cl-:1].[CH3:5][P+:6]1([CH2:2][CH2:3][OH:4])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CP1CCCC1
Reactant: OCCCl
Solvent: Cc1ccccc1
Product: C[P+]1(CCO)CCCC1
Product: [Cl-]

Procedure:
16.1 g (0.2 mole) of 2-chloroethanol were added to a solution of 20.4 g (0.2 mole) of 1-methyl-phospholane in 200 ml of toluene at room temperature, whilst stirring. The reaction mixture was then left to stand for some hours at room temperature and the precipitate which had separated out was then filtered off. This gave 1-methyl-1-(2-hydroxyethyl)-phospholanium chloride in the form of hygroscopic crystals of melting point 78°-80° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](Cl)(=[O:28])[C:25](Cl)=[O:26].[CH2:30]([OH:32])[CH3:31]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH:15]=2)[C:10]([C:24](=[O:28])[C:25]([O:32][CH2:30][CH3:31])=[O:26])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-c2ccc3ccn(Cc4ccccc4)c3c2)c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCO
Product: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2cc(-c3cccc(Cl)c3)ccc12

Procedure:
Ethyl [1-benzyl-6-(3-chlorophenyl)-1H-indol-3-yl](oxo)acetate was prepared from 1-benzyl-6-(3-chlorophenyl)-1H-indole (0.591 g, 1.86 mmol), oxalyl chloride (0.49 mL, 5.6 mmol), and ethanol (2 mL) following the procedure described in Step 3 of Example 1. Purification by flash chromatography using 5-100% ethyl acetate in hexane as an eluant yielded the title compound as a hard reddish gum (0.520 g, 67%). Mass spectrum (+ESI, [M+H]+) m/z 418; 1HNMR (500 MHz, DMSO-d6): δ 8.7 (s, 1H), 8.25 (d, 1H, J=8.2 Hz), 8.0 (s, 1H), 7.8 (s, 1H), 7.65-7.0 (m, 2H), 7.5 (t, 1H, J=7.9 Hz), 7.4 (d, 1H, J=0.92 Hz), 7.35-7.4 (m, 4H), 7.25-7.3 (m, 1H), 5.7 (s, 2H), 4.35 (q, 2H, J=7.1 Hz), and 1.35 ppm (t, 3H, J=7.2 Hz).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][C:14]=1[F:22]>C1COCC1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH3:8])[CH2:20][O:21]2)=[CH:15][C:14]=1[F:22]
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccc(Cl)c(F)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(c2ccc(Cl)c(F)c2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(4-chloro-3-fluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: C(N)=S.C(Cl)Cl.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][NH:18][C:19](=S)[SH-:20][CH2:21]C2C=CC=CC=2)=[CH:8]1.CCCCCCS/C(/S)=N\CC1NC2C=CC=CC=2C=1>CC#N.O>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[N:18]=[CH:19][S:20][CH:21]=2)=[CH:8]1
Reactant: S=C(NCCc1c[nH]c2ccccc12)[SH-]Cc1ccccc1
Agent: CCCCCCS/C(S)=N\Cc1cc2ccccc2[nH]1
Agent: NC=S
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: c1ccc2c(Cc3cscn3)c[nH]c2c1
Yield: 71 %

Procedure:
The general method was used with thioformamide to afford a 71% yield (Londergan et al. (1953) J. Am. Chem. Soc., 75:4456-8). 1H NMR (CDCl3) δ 8.76 (d, 1H, SCHN, J=2.0 Hz), 8.11 (br s, 1H, NH), 7.52 (d, 1H, ArH, J=7.6 Hz), 7.36 (d, 1H, ArH, J=8.0 Hz), 7.18 (t, 1H, ArH, J=7.1 Hz), 7.08 (t, 2H, ArH, J=7.4 Hz), 6.90 (s, 1H, ArH), 4.34 (s, 2H, ArCH2). 13C NMR (CDCl3) δ 157.5, 152.5, 122.5, 122.1, 119.4, 119.1, 113.8, 113.5, 111.2, 27.6. IR (CH2Cl2) vmax cm−1: 3626, 3470, 3051, 2987, 1420, 1264. GC: r.t.=15.05 min. EI-MS m/z (%) 214 (100, M+), 213 (86), 186 (15), 154 (14), 130 (51). RP-HPLC (1/1 CH3CN/H2O+0.1% TFA) r.t.=4.408 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:37])[CH:8]([N:15]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[N:17]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:16]2=[O:36])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.C(OC([N:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1)=O)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]2[N:17]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)(=[O:27])=[O:26])[C:16](=[O:36])[N:15]([CH:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:7](=[O:37])[N:4]3[CH2:5][CH2:6][CH:2]([NH:1][CH:48]4[CH2:49][CH2:50][NH:45][CH2:46][CH2:47]4)[CH2:3]3)[C:19]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCC(N)C3)c3ccccc3)c3cc(Cl)ccc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCC(NC4CCNCC4)C3)c3ccccc3)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 88.0 mg (0.16 mmol) of 3-[2-(3-aminopyrrolidin-1-yl)-2-oxo-1-phenylethyl]-5-chloro-1-(4-methoxybenzenesulfonyl)-1,3-dihydrobenzimidazol-2-one (example 166) in 5 ml of THF was mixed with 34.0 mg (0.17 mmol) of 1-tert-butoxycarbonyl-4-piperidone and 162 mg of MP-triacetoxyborohydride resin (Argonaut, 2.55 mmol/g, 0.41 mmol) and shaken at room temperature overnight. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated in vacuo, and the residue was dissolved in 3 ml of dichloromethane, mixed with 3 ml of trifluoroacetic acid and stirred at room temperature for 2 h. The solvent and excess trifluoroacetic acid were removed in vacuo, and the residue was taken up again in toluene and concentrated in vacuo. The residue was dissolved in dichloromethane, mixed with 3 eq. of MP-carbonate (Argonaut, 1.69 mmol/g) and stirred at room temperature for 2 h. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated under reduced pressure and dried in vacuo. The residue was purified by preparative RP-HPLC (mobile phase: gradient from 10% to 80% acetonitrile in water, 0.1% trifluoroacetic acid as modulator). Yield: 73.0 mg (72%) of colorless solid
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N=C=NC(C)C)(C)C.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:44]#[N:45])=[C:27]([C:29]2[C:34]([O:35][CH3:36])=[CH:33][N:32]([CH:37]([CH2:41][CH3:42])[C:38](O)=[O:39])[C:31](=[O:43])[CH:30]=2)[CH:28]=1.C(OC)(C)(C)C>CN(C)C=O.O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:44]#[N:45])=[C:27]([C:29]2[C:34]([O:35][CH3:36])=[CH:33][N:32]([CH:37]([CH2:41][CH3:42])[C:38]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=3)=[O:39])[C:31](=[O:43])[CH:30]=2)[CH:28]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)C(CC)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Temperature: 42.5 °C
Reaction time: 3 h

Procedure:
Under argon and at RT, 476 mg (2.9 mmol, 1.0 eq.) of ethyl 4-aminobenzoate and 41 mg (0.29 mmol, 0.1 eq.) of Oxima and then, dropwise, 452 μl (2.9 mmol, 1.0 eq.) of N,N′-diisopropylcarbodiimide (DIC) were added to a solution of 1.0 g (2.9 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) in 10 ml of dimethylformamide. The reaction mixture was stirred at 40-45° C. for 3 h and cooled to RT, methyl tert-butyl ether and water were added and the mixture was stirred vigorously for 10 min, resulting in the formation of a precipitate. The precipitate was filtered off, washed twice with water and methyl tert-butyl ether and dried under reduced pressure (precipitate 1). After phase separation of the combined filtrates, the aqueous phase was extracted once with methyl tert-butyl ether. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried (sodium sulphate), filtered and concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether, filtered, washed twice with methyl tert-butyl ether and dried under reduced pressure. This precipitate was stirred in aqueous hydrochloric acid (1N) for 10 min, filtered off, washed twice with water and once with acetonitrile and dried under reduced pressure (precipitate 2). Yield: precipitate 1: 1.12 g (79% of theory), precipitate 2: 127 mg (still contains 1,3-diisopropylurea according to 1H NMR)
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12]([O:20][CH2:21][CH2:22]Br)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[C:12]([O:20][CH2:21][CH2:22][O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: O=C(OCCBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(C)=O
Yield: 92.4 %

Procedure:
A mixture of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 15.7 g.), 2-bromoethyl benzoate (27.5 g.), potassium carbonate (20.7 g.), N,N-dimethylformamide (25 ml.) and ethyl acetate (25 ml.) was treated in a similar manner to that of Example A-(1) to give ethyl 2-(2-benzoyloxyethoxyimino)-3-oxobutyrate (syn isomer, 28 g.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([N+]([O-])=O)=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].Cl.COC(=O)[C@H:27]([CH2:44][CH2:45][S:46]C)NC(=O)C1C=CC(N)=CC=1C1C=CC=CC=1.[CH3:49][N:50]([CH:52]=O)C>C(=O)(O)[O-].[Na+]>[C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:46][C:45]2[CH:49]=[N:50][CH:52]=[CH:27][CH:44]=2)[C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)OC(=O)c1cccc(Sc2cccnc2)c1-c1ccccc1
Temperature: 100 °C
Reaction time: 60 h
Yield: 51 %

Procedure:
To a mixture in DMF (2 mL) of 4-nitro-2-phenylbenzoic acid tert-butyl ester (403 mg, 1.35 mmol), prepared by esterification of 4-nitro-2-phenylbenzoic acid (compound 8, step B), and 3-thiopyridine sodium salt (224 mg, 1.68 mmol), prepared as in 232C, was stirred at 100° C. for 60 hours. The reaction mixture was cooled to ambient temperature and diluted with saturated aqueous sodium bicarbonate. The mixture was extracted with ether (3×). The combined ether extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to give a brown oil. Chromatography on silica gel (10% ethyl acetate-hexanes) gave 3-pyridylthio-2-phenylbenzoic acid tert-butyl ester as a colorless oil (248 mg, 51%).
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[C:6]([N:12]2[CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][C:14](=O)[NH:13]2)=[N:7][CH:8]=[C:9]([Cl:11])[CH:10]=1.P(Br)(Br)([Br:25])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[Br:25][C:14]1[CH2:15][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:12]([C:6]2[C:5]([Cl:4])=[CH:10][C:9]([Cl:11])=[CH:8][N:7]=2)[N:13]=1
Reactant: CCOC(=O)C1CC(=O)NN1c1ncc(Cl)cc1Cl
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1CC(Br)=NN1c1ncc(Cl)cc1Cl
Reaction time: 0.33 h
Yield: 67 %

Procedure:
To a 250 mL flask, acetonitrile (65 mL), ethyl 2-(3,5-dichloropyridin-2-yl)-5-oxopyrazolidine-3-carboxylate (3.0 g, 9.8 mmol, the product of Step (3), Example 3) and phosphoryl bromide (2.8 g, 9.8 mmol) were added. The reaction mixture was heated to reflux for 2 hours. The reaction mixture was distilled to remove 30 mL solvent and added to the mixture of sodium carbonate (10 g, 120 mmol) and water (40 mL). The mixture was stirred for 20 minutes until no gas released. The reaction mixture was diluted with dichloromethane (100 mL), stirred for 50 minutes and extracted with dichloromethane (3×100 mL). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under vacuum to give the product (2.4 g) as amber oil in 67% yield. 1H NMR (300 MHz, CDCl3): 8.027 (d, 1H), 7.673 (d, 1H), 5.201 (dd, 1H), 4.202 (q, 2H), 3.464 (dd, 1H), 3.248 (dd, 1H), 1.223 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[C:11]([OH:34])=[C:10]([C:35]#[N:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[C:37]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[C:11]([O:34][CH3:37])=[C:10]([C:35]#[N:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(O)c(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1c(C#N)nc(-c2cncc(Cl)c2)c2c1nc(N1CCO[C@@H]3CCC[C@H]31)n2C[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-7-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (24.5 mg, 0.048 mmol) in DMF (2 mL) were added Cs2CO3 (31.5 mg, 0.097 mmol) and MeI (6 μL, 0.097 mmol). The reaction was stirred at room temperature for 15 minutes and then diluted with EtOAc (40 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified on a silica gel column with 0 to 100% EtOAc/hexanes to afford 4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-7-methoxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd for C28H33ClN6O2 [M+H]+=521. found=521.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C1C=CC=CC=1>[C:17]([N:1]1[CH:6]=[CH:5][CH:4]([C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[C:8]([F:7])[CH:9]=3)[NH:13][CH:12]=2)[CH:3]=[CH:2]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccncc1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: c1ccccc1
Product: O=C(c1ccccc1)N1C=CC(c2c[nH]c3ccc(F)cc23)C=C1
Reaction time: 8 h

Procedure:
To a stirred mixture of 100 parts of pyridine, 53 parts of 5-fluoro-1H-indole and 270 parts of benzene were added dropwise 57 parts of benzoyl chloride. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured onto a dilute hydrochloric acid solution and the layers were separated. The organic phase was dried, filtered and evaporated. The residue was purified twice by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 80 parts of 1-benzoyl-4-(5-fluoro-1H-indol-3-yl)-1,4-dihydropyridine as a residue (intermediate 19).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][OH:15])=[CH:11][C:10]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[O:17])=[C:9]2[CH3:29])=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH:14]=[O:15])=[CH:11][C:10]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[O:17])=[C:9]2[CH3:29])=[C:4]([C:30]([F:31])([F:33])[F:32])[CH:3]=1
Reactant: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cc(CCO)n1-c1ccc(Cl)cc1C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cc(CC=O)n1-c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a solution of the compound (1.0 g, 2.0 mmol) of Example 1 in dichloromethane (10 mL), Dess-Martin reagent (1.3 g, 3.0 mmol) was added at 0° C. The reaction temperature was raised to room temperature, and after the mixture was further stirred for 1 hour, it was diluted with ethyl acetate and the organic layer was washed with an aqueous sodium hydrogencarbonate solution, an aqueous sodium thiosulfate solution, water and saturated brine. After the solution was dried with sodium sulfate, it was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 1-[4-chloro-2-(trifluoromethyl)phenyl]-2-methyl-N-[4-(methylsulfonyl)phenyl]-5-(2-oxoethyl)-1H-pyrrole-3-carboxamide (0.85 g, 85%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[O:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(OC2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OC2CCOCC2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
To a solution of methyl 4-((tetrahydro-2H-pyran-4-yl)oxy)benzoate (400 mg, 1.6 mmol) in MeOH (10 ml) was added a solution of NaOH (128 mg, 3.2 mmol) in H2O (4 mL) at 22° C. The mixture was stirred at 50° C. for 4 h. The mixture was concentrated and the residue was treated with water and extracted with EA. The water layer was treated with 2N HCl to pH=3. The water layer was then extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give the title product which was used in next step without further purification (350 mg, Yield 98.6%). 1H NMR (CDCl3, 400 MHz): δ 8.08 (d, J=8.9 Hz, 2H), 6.98 (d, J=8.9 Hz, 2H), 4.64 (tt, J=7.7, 3.8 Hz, 1H), 3.95-4.09 (m, 2H), 3.64 (ddd, J=11.6, 8.2, 3.3 Hz, 2H), 2.01-2.13 (m, 2H), 1.78-1.93 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(Br)ccc(O)c1C(=O)O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Br)c(C)c1C(=O)O
Reaction time: 16 h

Procedure:
A mixture of 1B (6.93 g, 30 mmol), acetic anhydride (3.5 ml, 36 mmol) and pyridine (15 ml) is heated under reflux with stirring for 16 hours. The reaction mixture is diluted with water and ethyl acetate. The organic phase is acidified with dilute hydrochloric acid and washed with water twice. The organic phase is concentrated in vacuo and the residue is purified by flash chromatography (dichloromethane:methanol, 9:1 v/v) yielding the pure product as a yellow oil, 7.4 g, (90.3%).