Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11](O)=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:14][CH:15]1[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]1.CC[N:25](CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N.CO>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:25])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:14][CH:15]1[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(Br)cc2c(CC3CCS(=O)(=O)CC3)c[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1cc(Br)cc2c(CC3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To a solution of 5-bromo-3-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]-1H-indole-7-carboxylic acid (1.2 g, 3.22 mmol) in CH2Cl2 (100 mL) was added Et3N (650 mg, 6.44 mmol), TBTU (2.1 g, 6.44 mmol), and NH3/MeOH (10 mL). The mixture was stirred for 2 hours at room temperature. The reaction solution was washed with water, and the organic phase was dried (MgSO4), concentrated, and purified by column chromatography on silica gel, giving 770 mg (65%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][N:5]([CH3:7])[CH:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[F:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([C:8]([NH:22][C:23]2[CH:24]=[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]5[CH2:41][CH2:40]5)=[O:38])[N:35]=4)[N:32]=3)[CH:42]=[CH:43][C:44]=2[F:45])=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Cl)c(C(=O)O)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cn1cc(Cl)c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)n1
Yield: 80.2 %

Procedure:
In the same manner as in Example 259 and using 4-chloro-1-methyl-1H-pyrazole-3-carboxylic acid (130 mg, 0.79 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (170 μL, 2.0 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.61 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (230 mg, 80%) was obtained as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CCN(C(C)C)C(C)C.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(Cl)Cl>[CH3:1][N:2]([CH3:3])[S:22]([C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=1)(=[O:23])=[O:24]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To the solution of dimethylamine (284 mg, 6.3 mmol, 1.5 equiv.) and DIPEA (1 mL) in DCM (15 mL) was added dropwise a solution of 4-nitrobenzene-1-sulfonyl chloride (800 mg, 4.2 mmol, 1.0 equiv.) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 h. Then, the reaction mixture was washed with water and brine. The organic layers was dried (Na2SO4) and concentrated to get the residue, which was washed with isopropyl ether to afford compound N,N-dimethyl-4-nitrobenzenesulfonamide (879 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[N+:26]([O-])=O)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.CO.[H][H]>[Ni].O1CCCC1>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][CH2:18][CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][CH:10]([N:6]2[C:5]3[CH:29]=[CH:30][C:2]([Cl:1])=[CH:3][C:4]=3[NH:8][C:7]2=[O:9])[CH2:15][CH2:14]1
Reactant: [H][H]
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCNc2ccccc2[N+](=O)[O-])CC1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccccc1NCCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Yield: 70.5 %

Procedure:
A mixture of 64 parts of 5-chloro-1,3-dihydro-1-{1-[3-(2-nitrophenylamino)propyl]-4-piperidinyl}-2H-benzimidazol-2-one in 200 parts of methanol and 225 parts of tetrahydrofuran is hydrogenated at normal pressure and at room temperature with 10 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off over hyflo and the filtrate is evaporated. The residue is crystallized from a mixture of 2-propanol and ethanol. The product is filtered off and dried, yielding 42 parts (70.5%) of 1-[1-{3-[N-(2-aminophenyl)amino]propyl}-4-piperidinyl]-5-chloro-1,3-dihydro-2H-benzimidazol-2-one; mp. 196° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][NH:14][C:15](=O)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O.C(#N)C>CN(C=O)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([Cl:21])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2c1CN(Cc1ccccc1)CC2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Temperature: 70 °C
Yield: 57.8 %

Procedure:
A mixture of 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one (5.0 g, 0.02 mol), phosphoryl chloride (3.30 mL, 0.035 mol) and acetonitrile (80 mL) and DMF (catalytic amount) was heated at 70° C. for 1 hour. The mixture was concentrated in vacuo and the remaining black residue was taken up in dichloromethane (250 mL) and poured over ice. The mixture was carefully neutralized with the addition of solid sodium bicarbonate. The organic layer was separated and dried over sodium sulfate and concentrated in vacuo. The mixture was purified by silica gel column with EtOAc/hexane (0-100%) to yield the title compound as a yellow oil (3 g, 57.8%).
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][O:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].[C:24]([O:27][CH2:28]C)(=O)[CH3:25]>CN(C=O)C>[CH3:13][O:14][CH2:15][CH2:16][O:1][C:2]1[C:11]([O:12][CH2:25][CH2:24][O:27][CH3:28])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(O)c1O
Reactant: CCOC(C)=O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cccc(C(=O)OC)c1OCCOC
Temperature: 60 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A mixture of methyl 2,3-dihydroxybenzoate (2.18 g, 12.97 mmol), 2-bromoethyl methyl ether (4.50 g, 32.42 mmol), and potassium carbonate (6.91 g, 50.0 mmol) in DMF (20 mL) was stirred at 60° C. for 16 h. The reaction mixture was diluted with ethyl acetate (300 mL), washed with 5% aqueous LiCl (2×50 mL), and brine (50 mL), dried with sodium sulfate, and concentrated to provide crude methyl 2,3-bis{[2-(methyloxy)ethyl]oxy}benzoate (3.49 g, 95% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) δ7.32 (dd, 1H), 7.05 (m, 2H), 4.22 (m, 2H), 4.15 (m, 2H), 3.88 (s, 3H), 3.75 (m, 4H), 3.43 (s, 6H).
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH2:6][C@H:7]2[O:13][CH:11]([OH:12])[C@H:10]([OH:14])[C@@H:9]([OH:15])[C@H:8]2[OH:16])[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12.C(O[C:27](=[O:29])[CH3:28])(=O)C>N1C=CC=CC=1>[C:11]([O:12][CH:11]1[O:13][C@H:7]([CH2:6][N:5]2[C:4](=[O:17])[C:3]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]3[C:1]2=[O:22])[C@H:8]([O:16][C:27](=[O:29])[CH3:28])[C@H:9]([O:15][C:9](=[O:15])[CH3:8])[C@H:10]1[O:14][C:7](=[O:13])[CH3:6])(=[O:12])[CH3:10]
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1O[C@H](CN2C(=O)c3ccccc3C2=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 96 %

Procedure:
6-Deoxy-6-phthalimido-D-galactopyranose (2.9 g.) is acetylated with acetic anhydride (12 ml.) in pyridine (20 ml.) in the normal manner to give 1,2,3,4-tetra-O-acetyl-6-deoxy-6-phthalimido-D-galactopyranose (4.30 g., 96%) as a mixture of α- and β-anomers in the ratio of 1:1.6, [α]D27 +52.5° C. (C 1.0, chloroform); n.m.r. (chloroform-d): δ 5.70 (d, J1,2 8.0 Hz, H-1β), 6.33 (b, H-1α).
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH2:5][CH2:6]I)#[N:2].C(=O)([O-])[O-].[K+].[K+].[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:27][SH:28].O>CN(C)C=O>[C:1]([C:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH2:5][CH2:6][S:28][CH2:27][C:26]([O:30][CH2:31][CH3:32])=[O:29])#[N:2]
Reactant: N#CC(CCCI)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CSCCCC(C#N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.6 %

Procedure:
To a solution of 4-cyano-4,4-diphenyl iodobutane (0.4 g, 1.1 mmol.) in N,N-dimethylformamide (3 ml) were added potassium carbonate (0.31 g, 2,2 mmol.) and ethyl thioglycolate (0.14 g, 1.2 mmol.). The mixture was stirred for 15 hours at room temperature. To the reaction mixture was added water, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography, eluting with hexane - ethyl acetate (4:1) to afford the title compound (0.22 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)[CH3:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[K+].[Br-]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([O:12][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:6]=1)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
Ethyl-3,4-dihydroxy benzoate, 4 (27.3 g, 150 mmol), benzyl bromide (40.4 mL, 340 mmol) and potassium carbonate (41.4 g, 300 mmol) in acetone (350 mL) were reacted in a similar manner as described for 8 to afford 9. Yield 41.4 g (76%); mp 68-69° C.; MS (FAB) 363 (M++1); IR (KBr) 1889, 1707; 1H NMR (200 MHz, CDCl3) δ 7.65 (s, 1H), 7.63 (dd, J=8.7 Hz, 1.7 Hz, 1H), 7.48-7.25 (m, 10H), 6.91 (d, J=8.3 Hz, 1H), 5.19 (s, 2H), 5.18 (s, 2H), 4.31 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)[CH:3]=[CH2:4].[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1)[CH2:24][CH3:25])[CH3:22]>>[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:4][CH2:3][C:2]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:1])[CH2:24][CH3:25])[CH3:22]
Reactant: CCN(CC)CC1CCCCN1
Reactant: C=CC(=O)N1c2ccccc2NC(=O)c2ccccc21
Product: CCN(CC)CC1CCCCN1CCC(=O)N1c2ccccc2NC(=O)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 1h from 5,10-dihydro-5-(1-oxopropen-1-yl)-11H-dibenzo[b,e][1,4]diazepin-11-one and 2-[(diethylamino)methyl]piperdine to give colorless crystals mp. 125°-127° C. (acetonitrile).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH2:9][NH2:10]>N1C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:9][NH2:10])=[N:3][CH:4]=1
Reactant: NN
Reactant: Brc1ccc(Br)nc1
Solvent: c1ccncc1
Product: NNc1ccc(Br)cn1
Temperature: 85 °C

Procedure:
A mixture of 2,5-Dibromo-pyridine (13 g, 55.1 mmol) and hydrazine (13 mL, 414 mmol) in pyridine (13 mL) was heated at 85° C. for 48 hours. The reaction was cooled and concentrated in vacuo. The residue was triturated in 1N NaOH (20 mL) and toluene (20 mL). The solid was filtered, washed with water, and dried to give the above named compound (6.43 g, 62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][C@H:21]([NH:23][C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:25])[CH:20]([NH:32][CH3:33])[CH2:19]1)=[O:17].C(N(C(C)C)C(C)C)C.[S:43](Cl)([CH3:46])(=[O:45])=[O:44]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH2:22][C@H:21]([NH:23][C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:25])[CH:20]([N:32]([S:43]([CH3:46])(=[O:45])=[O:44])[CH3:33])[CH2:19]1)=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CNC1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(C1CC(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-chloro-thiophene-2-carboxylic acid {(S)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-methylamino-cyclopentyl}-amide (36 mg) in acetonitrile (2 ml) were added N-ethyldiisopropylamine (0.03 ml) and mesyl chloride (0.01 ml). The reaction mixture was stirred at r.t. for 3 hrs, then concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 92:8) to give 5-chloro-thiophene-2-carboxylic acid [(S)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-(methanesulfonyl-methyl-amino)-cyclopentyl]-amide (32 mg) as off-white solid. MS 567.2 ([M+H]+).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:17])(=[O:16])[N:13]([CH3:15])[CH3:14])[CH:6]=1)=O.[CH3:18][NH:19][C:20](=[S:30])[NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[CH3:29].C(OCC)(=O)C.C(OC(C)C)(C)C>C(O)(=O)C>[BrH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:19]([CH3:18])[C:20](=[N:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[CH3:29])[S:30][CH:2]=2)=[CH:6][C:7]=1[S:12](=[O:17])(=[O:16])[N:13]([CH3:15])[CH3:14]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: CNC(=S)Nc1ccc(C)cc1C
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: Br
Product: Cc1ccc(N=c2scc(-c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)n2C)c(C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3.41 g (0.01 mole) of 2-bromo-4'-chloro-3'-dimethylsulfamoyl-acetophenone are added to a solution of 1.83 g (0.01 mole) of 3-methyl-1-(2,4-dimethylphenyl)thiourea in 60 ml of glacial acetic acid and the mixture is stirred at room temperature for 20 minutes. It is then boiled for 20 minutes under a reflux condenser and allowed to cool, 60 ml of ethyl acetate or diisopropyl ether are added to the reaction mixture and the crystals are filtered off. Melting point 260°-264° C. (with decomposition).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:3][O:4][C:5](=[O:13])[C:6]1[C:11]([Br:1])=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=1
Reactant: COC(=O)c1ccnc(N)c1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(N)ncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Bromine (1.78 ml, 34.8 mmol) was added dropwise over an hour to a stirred solution of 2-amino-isonicotinic acid methyl ester (5.13 g, 33.75 mmol) in chloroform (350 ml) at room temperature and the orange solution stirred at room temperature overnight. A 2N solution of sodium thiosulfate (300 ml) was added to the reaction and stirred for ten minutes. The two layers were separated and the aqueous extracted with chloroform (100 ml). The combined organics were dried (MgSO4) and concentrated under reduced pressure. The desired isomer was purified by flash column chromatography using ethyl acetate 2/3 hexane as eluent to afford 2-amino-5-bromo-isonicotinic acid methyl ester as a yellow solid (1.79 g, 23%). 1H NMR (CDCl3): 8.21 (1 H, s, py); 6.79 (1 H, s, py); 4.53 (2 H, br s, NH2); 3.88 (3 H, s, CO2CH3).
Reaction SMILES: [F:1][CH:2]([F:22])[CH:3]([C:5]1[CH:6]=[C:7]([C:19](O)=[O:20])[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:10]=1)[OH:4].[CH3:23][C:24]1[N:28]=[C:27]([C@H:29]([NH2:31])[CH3:30])[O:26][N:25]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][CH:2]([F:22])[CH:3]([C:5]1[CH:6]=[C:7]([C:19]([NH:31][C@@H:29]([C:27]2[O:26][N:25]=[C:24]([CH3:23])[N:28]=2)[CH3:30])=[O:20])[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:10]=1)[OH:4]
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)cc(C(O)C(F)F)c1
Reactant: Cc1noc([C@@H](C)N)n1
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1noc([C@@H](C)NC(=O)c2cc(-c3ccc(F)cc3F)cc(C(O)C(F)F)c2)n1
Reaction time: 2 h
Yield: 59.3 %

Procedure:
To a solution of 5-(2,2-difluoro-1-hydroxyethyl)-2′,4′-difluorobiphenyl-3-carboxylic acid (0.25 g, 0.80 mmol) in N,N-dimethylformamide (2.7 mL) were added (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine (0.18 g, 0.88 mmol), EDC (0.27 g, 1.39 mmol), HOAT (51.1 mg, 0.40 mmol) and triethylamine (0.67 mL, 4.77 mmol). The mixture was stirred at 50 C. After 2 h, saturated sodium bicarbonate was added the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→85% dichloromethane/methanol). Product obtained was not pure therefore it was purified again by reverse phase chromatography (C-18, 95% water/acetonitrile→30% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (201 mg). HRMS 424.1283 (M+1). 1H NMR δ (ppm) (DMSO-d6): 9.28 (1H, d, J=7.3 Hz), 8.01 (2H, s), 7.76 (1H, s), 7.66 (1H, dd, J=15.6, 9.0 Hz), 7.43 (1H, m), 7.26 (1H, m), 6.11 (1H, dt, J=11.2, 0.7 Hz), 5.40 (1H, m), 4.93 (1H, m), 2.33 (3H, s), 1.61 (3H, d, J=7.3 Hz).
Reaction SMILES: [F:1][CH2:2][CH2:3]I.CN(C)C=O.[C:10]([O:14][C:15](=[O:44])[C@@H:16]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:17][CH2:18][CH:19]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:13])([CH3:12])[CH3:11].O>C(OCC)(=O)C>[C:10]([O:14][C:15](=[O:44])[C@@H:16]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:17][CH2:18][CH:19]([CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:3][CH2:2][F:1])=[CH:33][CH:34]=1)[C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])([CH3:11])([CH3:12])[CH3:13]
Reactant: FCCI
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(CCc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(CCc1ccc(OCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 60.2 %

Procedure:
53 mg (0.30 mmol) 1-Fluoro-2-iodoethane were dissolved in 5 ml dimethylformamide 98 mg (0.71 mmol) potassium carbonate and 100 mg (0.20 mmol) (2S,5RS)-2-tert.-Butoxycarbonylamino-5-[2-(4-hydroxy-phenyl)-ethyl]-hexanedioic acid di-tert.-butyl ester added. The mixture was stirred at room temperature over night. For workup, water and ethyl acetate were added, the phases separated and the water extracted with ethyl acetate twice. Combined organic phases were dried (Na2SO4), filtered and evaporated. The raw product was absorbed on Isolute and chromatographed on a Biotage Isolera system (SNAP NH 110 g, A=n-hexane, B=ethyl acetate, A 2 CV, A to 47% B in 9.4 CV, 5 CV 50% B, 50 mL/min, Fr. a 22 mL). Fractions 29 to 32 were collected to give 65 mg (59%) of (2S,5RS)-2-tert.-Butoxycarbonylamino-5-{2-[4-(2-fluoro-ethoxy)-phenyl]-ethyl}-hexanedioic acid di-tert.-butyl ester as clear oil.
Reaction SMILES: [Cl-].[NH4+:2].[C-:3]#[N:4].[Na+].N.[CH3:7][C:8]([C:11]1[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH:17]=O)=[CH:13][CH:12]=1)([CH3:10])[CH3:9]>CO.O>[NH2:2][CH:17]([CH2:16][O:15][C:14]1[CH:19]=[CH:20][C:11]([C:8]([CH3:10])([CH3:9])[CH3:7])=[CH:12][CH:13]=1)[C:3]#[N:4]
Reactant: [NH4+]
Reactant: [C-]#N
Reactant: CC(C)(C)c1ccc(OCC=O)cc1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(OCC(N)C#N)cc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2.92 g (54.6 mmol.) of ammonium chloride, 2.47 g (50.4 mmol.) of sodium cyanide and 18 ml (296 mmol.) of a 28% aqueous solution of ammonia, there was added dropwise a solution of the wet cake of 2-[4-(1,1-dimethylethyl)phenoxy]acetoaldehyde obtained in Production Example 9 in 8 ml of methanol with stirring at a temperature of 10° C. for 30 minutes. Then the reaction mixture was further stirred at the same temperature for 30 minutes. Then, the reaction mixture was stirred under an atmosphere of a gas of ammonia at room temperature for 2 days. After the reaction was completed, the resultant mixture was poured into cold water and extracted with ethyl acetate. The residue was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 3.89 g of 2-amino-3-[4-(1,1-dimethylethyl)phenoxy]propionitrile as a light-yellowish resinoid [60 MHz 1H-NMR (CDCl3, TMS), δ (ppm) 1.26(9H,s), 4.05(2H,d, J=5Hz), 4.63(1H,t, J=5Hz), 6.72(2H,d, J=10Hz), 7.21(2H,d, J=10Hz)].
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH:18]=[O:19])([C:14]([F:17])([F:16])[CH3:15])[C:4]=2[CH:3]=1.[CH:22]([O:31][CH:32]([CH3:34])[CH3:33])([O:27][CH:28]([CH3:30])[CH3:29])OC(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.O>C(O)(C)C.C(Cl)Cl>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH:22]([O:27][CH:28]([CH3:29])[CH3:30])[O:31][CH:32]([CH3:33])[CH3:34])([C:14]([F:17])([F:16])[CH3:15])[C:4]=2[CH:3]=1.[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH:18]=[O:19])([C:14]([F:16])([F:17])[CH3:15])[C:4]=2[CH:3]=1
Reactant: CC(C)OC(OC(C)C)OC(C)C
Agent: CC(F)(F)C1(C=O)c2cc(Cl)ccc2Nc2ncccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)OC(OC(C)C)C1(C(C)(F)F)c2cc(Cl)ccc2Nc2ncccc21
Reaction time: 18 h
Yield: 49 %

Procedure:
Method PP: To a stirred solution of 7-chloro-5-formyl-5-(1,1-difluoroethyl)-5,10-dihydrobenzo[b][1,8]naphthyridine (51) (619 mg, 2.005 mmol) in anhydrous triisopropyl orthoformate (30.0 mL, 134 mmol), anhydrous isopropanol (10 mL) and anhydrous methylene chloride (10 mL) at room temperature was added p-TsOH.H2O (763 mg, 4.010 mmol). After 18 h at room temperature, the reaction was quenched with saturated aqueous NaHCO3 (25 mL), and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (30%-40% EtOAc-hexane, gradient elution) afforded 53 (400 mg, 49% yield) as a yellow solid as well as 45% recovery of starting material 51 (280 mg).