Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C@H:17]([NH:23][C@@H:24]1[C:30](=[O:31])[N:29]([CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])[C:28]2[CH:40]=[CH:41][CH:42]=[CH:43][C:27]=2[O:26][CH2:25]1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=O)(C)(C)C.C(OCC)(=O)C.[ClH:50]>>[ClH:50].[ClH:50].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C@H:17]([NH:23][C@@H:24]1[C:30](=[O:31])[N:29]([CH2:32][C:33]([OH:35])=[O:34])[C:28]2[CH:40]=[CH:41][CH:42]=[CH:43][C:27]=2[O:26][CH2:25]1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)[C@H](CCCCCCCCNC(=O)OC(C)(C)C)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCCCCCN)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Reaction time: 2.5 h

Procedure:
A mixture of tert-butyl 3(S)-[9-tert-butoxycarbonylamino-1(S)-ethoxycarbonylnonyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.33 g) and 5N hydrogen chloride-ethyl acetate solution (8 ml) is allowed to stand for 2.5 hours at room temperature. The mixture is diluted with petroleum ether (80 ml) to deposit colorless powder, which is collected and dried under reduced pressure to give 3(S)-[9-amino-1(S)-ethoxycarbonylnonyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid dihydrochloride (0.25 g).
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[S:8][CH3:9].[CH3:10][N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12](Cl)=[O:13]>>[CH3:9][S:8][C:4]1[N:3]([O:2][C:12](=[O:13])[N:11]([CH3:10])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CSc1nccn1O
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: Cl
Product: CSc1nccn1OC(=O)N(C)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-2-methylsulfanyl-imidazole hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (97%, oil).
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH3:15])[CH:6]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>O1CCOCC1>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:2][C:3]#[C:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH3:15])[CH:6]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: COc1cc(C#CCCl)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: COc1cc(C#CCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 97.3 %

Procedure:
To 4-(3-chloro-1-propyn-1-yl)-2-(methyloxy)-1-nitrobenzene (Example 139, step B) (0.250 g, 1.1 mmol) in 10 mL of dioxane was added, 1-methylpiperazine (0.31 g, 3.1 mmol). The mixture was heated to 110° C. for 3 h. The mixture was purified by flash chromatography to give the title compound of step A (0.309 g, 1.07 mmol, 97%). 1H NMR (400 MHz, CDCl3) δ ppm 7.78 (d, J=8.24 Hz, 1H), 7.11 (s, 1H), 7.04 (dd, J=8.33, 1.56 Hz, 1H), 3.94 (s, 3H), 3.55 (s, 2H), 2.64-2.78 (m, 4H), 2.47-2.62 (m, 4H), 2.33 (s, 3H).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(O)=O.Br.[NH2:16][CH2:17][CH2:18][CH2:19][SH:20].C([O-])(=O)C.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:6]2[C:7](=[O:9])[N:16]3[CH2:17][CH2:18][CH2:19][S:20][C:1]3=[CH:4][C:5]=2[CH:13]=1
Reactant: NCCCS
Reactant: O=C(O)Cc1cc(Cl)ccc1C(=O)O
Agent: Br
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=c1c2ccc(Cl)cc2cc2n1CCCS2

Procedure:
By following the same procedure as in Example 13 using 0.32 g. of 2-carboxymethyl-4-chlorobenzoic acid, 0.37 g. of 3-aminopropanethiol hydrobromide, 0.172 g. of sodium acetate and 0.3 g. of p-toluensulfonic acid, 0.15 g. of 9-chloro-6-oxo-3,4-dihydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline was obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:18][CH3:19])/[C:14]([O:16]C)=[O:15].CCO.O>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:18][CH3:19])/[C:14]([OH:16])=[O:15]
Reactant: COC(=O)/C(=C/C=C/c1cc2ccccc2s1)OC
Solvent: CCO
Solvent: O
Product: CO/C(=C\C=C\c1cc2ccccc2s1)C(=O)O
Yield: 53.1 %

Procedure:
To a stirred solution of methyl (2Z,4E)-5-(benzothiophen-2-yl)-2-methoxy-2,4-pentadienoate (107 mg, 0.39 mmol) in EtOH/water 1/1 (10 ml) potassium hydroxide (47 mg, 0.78 mmol) was added. The solution was refluxed for 1 hour, then it was treated as seen in example 2. Pure title compound (54 mg, 0.207 mmol, yield 53.2%) was obtained as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.BrC1C=CC(Cl)=CC=1[CH2:21][O:22][CH2:23]OC>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[CH2:4][O:6][CH2:21][O:22][CH3:23]
Reactant: COCOCc1cc(Cl)ccc1Br
Reactant: COc1ccc(Br)c(C(=O)O)c1
Product: COCOCc1cc(OC)ccc1Br

Procedure:
This compound was made from 2-bromo-5-methoxybenzoic acid in the same manner as compound 18d: 1H NMR (300 MHz, DMSO-d6): δ 3.30 (s, 1H), 3.74 (s, 3H), 4.50 (s, 2H), 4.69 (s, 2H), 6.83 (dd, J=8.8, 2.9 Hz, 1H), 7.40 (d, J=2.9 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][NH2:12])[CH:9]=2)[CH:4]=[N:3]1.[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18]>CCO>[C:14]([C:15]1[CH:16]=[C:17]([NH2:18])[N:11]([C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[N:3][NH:2]3)=[CH:6][CH:7]=2)[N:12]=1)([CH3:21])([CH3:20])[CH3:13]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccc2cn[nH]c2c1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc3cn[nH]c3c2)n1
Yield: 58 %

Procedure:
A mixture of (1H-indazol-6-yl)-hydrazine hydrochloride and 4,4-dimethyl-3-oxo-pentanenitrile (17 g, 1.05 eq) in EtOH (200 mL) was heated at reflux overnight. The reaction was concentrated and the residue purified by column chromatography to yield 3-t-butyl-1-(1H-indazol-6-yl)-1H-pyrazol-5-amine (21 g, 58% yield, for two steps). 1H NMR (300 MHz, DMSO-d6): 8.21 (s, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.81 (s, 1H), 7.25 (d, J=8.1 Hz, 1H), 5.71 (s, 1H), 1.31 (s, 9H); MS (ESI) m/z: 256 (M+H+).
Reaction SMILES: [OH:1][N:2]([CH3:17])[C:3](=[NH:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[C:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])#[C:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH2:28]([O:27][C:25]([C:18]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:1][N:2]([CH3:17])[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:16]1)=[O:26])[CH3:29]
Reactant: CN(O)C(=N)c1ccccc1N1CCOCC1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CC1(C(=O)OCC)N=C(c2ccccc2N2CCOCC2)N(C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To a stirred solution of N-hydroxy-N-methyl-2-morpholin-4-yl-benzamidine (3.8 g) in ethanol (100 mL, 200 proof) was added diethyl acetylene-dicarboxylate (3.2 mL, 20 mmol) and the resulting mixture stirred at room temperature for 30 min. The mixture was then concentrated and purified on a silica gel column (10%–30% ethyl acetate/hexanes) to afford the title compound (3.64 g, 45% yield). 1HNMR (300 MHz, CDCl3) δ: 7.64 (1H, dd, J=7.69, 1.83 Hz), 7.40 (1H, td, J=8.05, 1.83 Hz), 7.02 (1H, t, J=7.32 Hz), 6.97 (1H, d, J=8.05 Hz) 4.31–4.20 (2H, m), 4.15 (2H, q, J=7.08 Hz), 3.88–3.74 (4H, m), 3.38 (1H, d, J=16.46 Hz), 3.12–2.92 (4H, m), 3.05 (3H, s), 3.03 (1H, d, J=16.47 Hz), 1.29 (3H, t, J=6.95 Hz), 1.25 (3H, t, J=6.96 Hz). HRMS (ESI) calcd for C20H28N3O6 (M+H): 406.1978; found: 406.1975.
Reaction SMILES: [C:1]([C:3]1([OH:18])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4]1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:2][CH2:1][C:3]1([OH:18])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4]1
Reactant: N#CC1(O)CCN(C(=O)OCc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1(O)CCN(C(=O)OCc2ccccc2)C1
Reaction time: 24 h
Yield: 53.4 %

Procedure:
To a stirred solution of phenylmethyl 3-cyano-3-hydroxy-1-pyrrolidinecarboxylate (0.92 g, 3.74 mmole), in THF (50 mL) at RT was added LiAlH4 (3.75 mL, 1M in THF). After 24 h, the reaction was quenched with H2O (0.15 mL), 20% NaOH (0.30 mL) and then H2O (0.35 mL). The reaction contents were filtered through a scinter-glass funnel and concentrated under vacuum to afford the title compound (0.50 g, 79%) as a yellow oil: LC-MS (ES) m/e 250 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Br[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[CH:16][N:15]=1>>[F:22][CH:21]([F:23])[O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)=[N:15][CH:16]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: FC(F)Oc1ccc(Br)nc1
Product: O=C(O)c1ccc(-c2ccc(OC(F)F)cn2)cc1

Procedure:
Operations similar to those of Production Example 14 were conducted using 4-carboxyphenylboronic acid and 2-bromo-5-(difluoromethoxy)pyridine, to provide the title compound as white solid.
Reaction SMILES: CS[C:3]1[C:4]2[C:5](=[CH:9][S:10][CH:11]=2)[N:6]=[CH:7][N:8]=1.[NH2:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1>C(O)C>[CH2:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH:13]1[NH:12][C:3]1[C:4]2[C:5](=[CH:9][S:10][CH:11]=2)[N:6]=[CH:7][N:8]=1
Reactant: NC1Cc2ccccc2C1
Reactant: CSc1ncnc2cscc12
Solvent: CCO
Product: c1ccc2c(c1)CC(Nc1ncnc3cscc13)C2
Yield: 22 %

Procedure:
4-methylthiothieno[3,4-d]pyrimidine (90 mg, 0.50 mmol) (see J. Heterocyclic Chem., 30, 509 (1993)) and 2-aminoindan (200 mg, 1.5 mmol) in dry ethanol (4 ml) were heated to reflux under an argon atmosphere for 4 hours. The solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel chromatography (ethyl acetate:methanol=20:1) to obtain the title compound (30 mg, 0.11 mmol) having the following physical properties;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=1.[C:21](OCC)(=[O:23])C.C(=O)(O)[O-].[Na+]>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH:20][CH:21]=[O:23])[CH:17]=[CH:18][CH:19]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(N)c2)C1
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC=O)c2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (600 mg, example 35) was dissolved in formic acid (2.4 ml) and kept for 15 min at reflux temperature. After standing over night an ice/water mixture was added followed by ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted 3 times with dichloromethane. The organic layers were combined, dried (magnesium sulphate), filtered and concentrated in vacuo to yield 588 mg of the title compound.
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6](=O)[C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[N:9][CH:8]=1)C>C(O)C>[Br:13][C:11]1[CH:12]=[C:7]([CH2:6][OH:5])[CH:8]=[N:9][CH:10]=1
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 34.6 %

Procedure:
Crushed pellets of sodium borohydride were added over 30 minutes to a solution of 5-bromonicotinic acid ethyl ester of Step A (5.0 g, 21.7 mmol) in ethanol (150 mL). The reaction was stirred at room temperature for five days and then quenched with water. The ethanol was removed under reduced pressure and the aqueous residue was extracted three times with methylene chloride. The combined organics were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to a yellow oil. The material was purified by flash chromatography over silica gel Marck-60 using 2:1 hexane/ethyl acetate as an eluant to give the title compound (1.41 g) as a light yellow liquid which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([CH2:8][C:9]([O:11]CC)=O)=O.[NH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[NH2:20]>C(O)C>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:19]1[C:9]([OH:11])=[CH:8][C:6]([C:5]2[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)=[N:20]1
Reactant: NNc1ccccn1
Reactant: CCOC(=O)CC(=O)c1cccc(C(F)(F)F)c1
Solvent: CCO
Product: Oc1cc(-c2cccc(C(F)(F)F)c2)nn1-c1ccccn1

Procedure:
Ethyl 3-trifluoromethylbenzoylacetate (10 mmol, manufactured by Aldrich) and ethanol (10 mL) were charged in a 100 mL round-bottom flask to which a solution of 2-hydrazinopyridine (10 mmol, manufactured by Aldrich) in ethanol (10 mL) was then added.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])([CH3:3])[CH3:2].C([Li])CCC.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.C(OCC)(=O)C.Cl>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:32])=[O:31])[CH:9]=[C:8]2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)Oc1ccc2[nH]cc(CCC(=O)O)c2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc2c(c1)c(CCC(=O)O)cn2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of propionic acid (27) (96.3 mg, 0.510 mmol) in tetrahydrofuran (10 ml), n-butyl lithium (1.40 ml, 2.24 mol) was added next and stirred for 30 minutes at −78° C. Benzene sulfonyl chloride (277 mg, 1.5 mmol) was added next, and the reaction was stirred for 16–24 hours, allowing temperature to rise from −78° C. to ambient conditions. The reaction was then diluted with ethyl acetate, and 1M HCl was added to adjust the pH to 1–2. The layers were then separated, and the organic layer was placed over magnesium sulfate and concentrated under reduced pressure. The crude material was then purified by flash chromatography with silica, eluting with 5% methanol in dichloromethane to yield the desire product (22) as a white solid. (M−1=386.4)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](S(C3C=CC=CC=3)=O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C1([Mg]Br)C=CC=CC=1.[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.[NH4+].[Cl-]>C1COCC1>[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]([C:7]2[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[CH:9][CH:8]=2)[OH:35])=[CH:32][CH:31]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COc1ccc2c(S(=O)c3ccccc3)ccnc2c1
Agent: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2c(C(O)c3ccc(Br)cc3)ccnc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
In a 100 mL round bottom flask under N2, was dissolved 7-methoxy-4-(phenylsulfinyl)quinoline (650 mg, 2.29 mmol) in 10 mL of THF and then the solution was cooled to −78° C. and treated with PhMgBr (3M in Et2O) (1.50 mL, 4.59 mmol). The reaction mixture was then warmed to rt. After 30 min, the mixture was cooled again to −78° C., and solid 4-bromobenzaldehyde (1.27 g, 6.88 mmol) was added. Then, the reaction mixture was warmed to rt. After 2 h the reaction mixture was neutralized with aqueous NH4Cl (sat). The aqueous phase was extracted three times with dichloromethane, and then the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by MPLC (ISCO dichloromethane:MeOH 100:0 to 90:10) to afford (4-bromophenyl)(7-methoxyquinolin-4-yl)methanol (540 mg, 68.4% yield) as a yellow solid. MS (ESI pos. ion) m/z: 345 (M2H+). Calc'd exact mass for C17H14BrNO2: 343. 1H NMR (400 MHz, CDCl3) 8.83 (d, J=4.42 Hz, 1H), 7.81 (d, J=9.35 Hz, 1H), 7.53 (d, J=4.42 Hz, 1H), 7.44-7.49 (m, 3H), 7.25 (d, J=8.34 Hz, 2H), 7.14 (dd, J=9.28, 2.59 Hz, 1H), 6.43 (s, 1H), 3.93 (s, 3H).
Reaction SMILES: C(OC(N1CCCC1C1NC(C2C=CC(C3C=CC(C4NC(C5CCN(C(OC(C)(C)C)=O)C5)=NC=4)=CC=3)=CC=2)=CN=1)=O)(C)(C)C.[CH3:47][O:48][C:49](=[O:84])[NH:50][CH:51]([C:55]([N:57]1[CH:62]([C:63]2[NH:64][C:65]([C:68]3[CH:73]=[CH:72][C:71](B4OC(C)(C)C(C)(C)O4)=[CH:70][CH:69]=3)=[CH:66][N:67]=2)[CH:61]2[CH2:83][CH:58]1[CH2:59][CH2:60]2)=[O:56])[CH:52]([CH3:54])[CH3:53].[CH3:85][O:86][C:87](=[O:114])[NH:88][CH:89]([C:93]([N:95]1[CH:100]([C:101]2[NH:102][C:103]([C:106]3[CH:111]=[CH:110][C:109](Br)=[CH:108][CH:107]=3)=[CH:104][N:105]=2)[CH:99]2[CH2:113][CH:96]1[CH2:97][CH2:98]2)=[O:94])[CH:90]([CH3:92])[CH3:91].C(OC(N1CCCC1C1NC(C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=CN=1)=O)(C)(C)C.C(OC(N1CCC(C2NC(C3C=CC(Br)=CC=3)=CN=2)C1)=O)(C)(C)C>>[CH3:85][O:86][C:87](=[O:114])[NH:88][CH:89]([C:93]([N:95]1[CH:100]([C:101]2[NH:102][C:103]([C:106]3[CH:107]=[CH:108][C:109]([C:71]4[CH:72]=[CH:73][C:68]([C:65]5[NH:64][C:63]([CH:62]6[CH:61]7[CH2:60][CH:59]([CH2:58][CH2:83]7)[N:57]6[C:55](=[O:56])[CH:51]([NH:50][C:49]([O:48][CH3:47])=[O:84])[CH:52]([CH3:53])[CH3:54])=[N:67][CH:66]=5)=[CH:69][CH:70]=4)=[CH:110][CH:111]=3)=[CH:104][N:105]=2)[CH:99]2[CH2:113][CH:96]1[CH2:97][CH2:98]2)=[O:94])[CH:90]([CH3:92])[CH3:91]
Reactant: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Agent: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)cc3)[nH]2)C1
Agent: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Agent: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Product: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5C6CCC(C6)N5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C

Procedure:
Following the procedure used to prepare compound 2-(5-{4′-[2-(1-Boc-pyrrolidin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester, except that [2-methyl-1-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]-carbamic acid methyl ester and (1-{3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester were used instead of 2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester and 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester. 1H-NMR (300 MHz, CD3OD) δ 7.90-7.20 (m, 10H), 4.83-4.25 (m, 5H), 3.90-3.40 (m, 6H), 2.90-2.70 (m, 2H), 2.40-2.10 (m, 3H), 2.10-1.40 (m, 11H), 1.10-0.90 (m, 12H); m/z 791.3 (M+H)+.
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:13]([C:26]([O:28]CC)=[O:27])=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[N:1]1([C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:13]([C:26]([OH:28])=[O:27])=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1OCc1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(COc2nc(N3CCc4ccccc43)ncc2C(=O)O)cc1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
To a suspension of ethyl 2-(2,3-dihydro-1H-indol-1-yl)-4-[(4-methoxybenzyl)oxy]-5-pyrimidinecarboxylate (5.5 g, 13.6 mmol) in ethanol (50 mL) were added 10% aqueous sodium hydroxide solution (30 mL) and tetrahydrofuran (30 mL) and the mixture was heated under reflux for 30 min. The reaction mixture was allowed to cool to room temperature and 1N hydrochloric acid was added to adjust the reaction mixture to pH 5. The precipitated crystals were collected by filtration, washed several times with water, and dried with heating under vacuum to give 2-(2,3-dihydro-1H-indol-1-yl)-4-[(4-methoxybenzyl)oxy]-5-pyrimidinecarboxylic acid (4.9 g, 96%) as crystals. A suspension of the obtained carboxylic acid (564 mg, 1.5 mmol), L-α-amino-ε-caprolactam (384 mg, 3.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (612 mg, 3.0 mmol) and 1-hydroxybenzotriazole (408 mg, 3.0 mmol) in dichloromethane (2 mL) was stirred at room temperature for 18 h. Water and ethyl acetate were added to the reaction mixture and the organic layer was concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography and eluted with ethyl acetate to give the title compound (650 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:33])=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:29])[CH2:16][N:17]1[C:21]2=[CH:22][N:23]=[CH:24][CH:25]=[C:20]2[C:19]([C:26]([NH2:28])=[O:27])=[N:18]1)=[O:8].ClC1C=C(C=CC=1)C(OO)=[O:39]>C(O)(=O)C>[C:26]([C:19]1[C:20]2[C:21](=[CH:22][N+:23]([O-:39])=[CH:24][CH:25]=2)[N:17]([CH2:16][C:15]([N:10]2[C@H:9]([C:7](=[O:8])[NH:6][CH2:5][C:4]3[CH:30]=[CH:31][CH:32]=[C:2]([Cl:1])[C:3]=3[F:33])[CH2:14][C@@H:13]3[C@H:11]2[CH2:12]3)=[O:29])[N:18]=1)(=[O:27])[NH2:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cnccc12
Solvent: CC(=O)O
Product: NC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2c[n+]([O-])ccc12
Temperature: 55 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(2-((1R,3S,5R)-3-(3-chloro-2-fluorobenzylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 703, 100 mg, 0.21 mmol) in acetic acid (4 mL) was added 3-chlorobenzoperoxoic acid (58 mg, 0.34 mmol) at 55° C. The reaction mixture was stirred at 55° C. for 18 h and then cooled to RT. Volatiles were evaporated and the residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to afford the title compound as a white solid. MS: 487 [M+H]+; tR (HPLC conditions c): 3.44 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=1.[CH3:12][O:13][C:14](=[O:20])[NH:15][C:16](=O)[CH2:17]Cl>CN(P(N(C)C)(N(C)C)=O)C>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:17]=[C:16]([NH:15][C:14]([O:13][CH3:12])=[O:20])[N:1]=2)[CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(N)nc1
Reactant: COC(=O)NC(=O)CCl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)Nc1cn2cc(S(C)(=O)=O)ccc2n1

Procedure:
A suspension of 2-amino-5-(methylsulfonyl)pyridine (58.7 mmol) and methyl(chloroacetyl)carbamate (70 mmol) in 88 ml of HMPT is treated in a manner similar to that described above with respect to Example 1D to yield the product.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(#N)C>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: CNc1ccccc1
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N(C)c1ccccc1
Temperature: 100 °C
Yield: 64.2 %

Procedure:
N-methylaniline (2.88 ml, 26.6 mmol) was added to a solution of ethyl 2-bromo-2-phenylacetate (4.65 ml, 26.6 mmol) in acetonitrile (55 ml). The reaction was heated in sealed tube under microwave irradiation at 100° C. for 30 minutes. Acetonitrile was evaporated, residue was taken up with EtOAc and washed sequentially with 1N NaHCO3, 1N HCl and brine. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The residue was triturated with hexane and then purified by flash chromatography (Petroleum ether/EtOAc=97/3) to obtain ethyl 2-(methyl(phenyl)amino)-2-phenylacetate (4.6 g, 64.3% yield).