Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@H:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[N:4][CH:5]=[C:6]([C:7](=[O:8])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:21]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 93.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and (S)-tert-butyl (pyrrolidin-3-ylmethyl)carbamate. LC-MS (Condition 6) tR=2.7 min, m/z=559.0/561.0 [M+H]+, m/z=581.0 [M+Na]+.
Reaction SMILES: N(OC(C)(C)C)=O.[F:8][C:9]1[CH:34]=[CH:33][CH:32]=[CH:31][C:10]=1[CH2:11][N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[C:14]([C:21]2[N:22]=[C:23](N)[C:24]3[N:29]=[N:28][NH:27][C:25]=3[N:26]=2)=[N:13]1.O>CN(C)C=O>[F:8][C:9]1[CH:34]=[CH:33][CH:32]=[CH:31][C:10]=1[CH2:11][N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[C:14]([C:21]2[N:22]=[CH:23][C:24]3[N:29]=[N:28][NH:27][C:25]=3[N:26]=2)=[N:13]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]nnc12
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccccc1Cn1nc(-c2ncc3nn[nH]c3n2)c2cccnc21
Temperature: 65 °C
Yield: 1 %

Procedure:
570 mg (5.535 mmol) of tert-butyl nitrite were dissolved in 20 ml of dry dimethylformamide, and 1000 mg (2.767 mmol) of the compound from example 53 suspended in 15 ml of dimethylformamide were added at 65° C. by means of a syringe pump within 1 h. After stirring at 65° C. for a further hour, 100 ml of water were added, forming a precipitate. The precipitate was filtered off and purified by means of preparative HPLC (eluent: water/acetonitrile/water with 1% trifluoroacetic acid, gradient 64:20:16→0:100:0). 10 mg of the title compound were obtained (1% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[O:25][CH2:24][CH2:23][NH:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH:33]=O)=[CH:28][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[O:25][CH2:24][CH2:23][N:22]([CH2:33][CH2:32][C:29]4[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=4)[CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=CCc1ccccc1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C(=O)C2CNCCO2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C(=O)C2CN(CCc3ccccc3)CCO2)CC1

Procedure:
To a stirred solution of N-(3,4-dichlorophenyl)-4-(morpholin-2-ylcarbonyl)piperazine-1-carboxamide (350 mg) in dichloromethane (10 ml) under an argon atmosphere was added phenacetaldehyde (0.16 mL) then NaBH(OAc)3 (383 mg) and the reaction was stirred for 3.5 h. The solvent was then removed under reduced pressure and dissolved in dichloromethane (40 ml) and 1M NaOH (20 ml). The organic layer was separated, dried (MgSO4) and evaporated. Purification by column chromatography 3-7% MeOH:DCM afforded the title compound (170 mg) as a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=O.C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1.[BH4-].[Na+].Cl>C1COCC1.O>[OH:7][CH2:5][C:4]1[CH:8]=[CH:9][C:10]2[O:11][C:17](=[O:18])[NH:1][C:2]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(C(=O)O)ccc1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2cc(CO)ccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of 2.06 g of 3-amino-4-hydroxybenzoic acid in 20.6 ml of THF was added 4.81 g of CDI, followed by stirring at room temperature for 1 hour. The reaction mixture was added dropwise to a mixed liquid of 3.06 g of sodium borohydride in 20.6 ml of THF and 8.26 ml of water, cooled to 0° C., which had been separately prepared, followed by stirring overnight. 1 M hydrochloric acid was added thereto, followed by extracting with ethyl acetate, and washing with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 1.2 g of 5-(hydroxymethyl)-1,3-benzoxazol-2(3H)-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:24]3[CH:23]=[C:22]([Cl:21])[CH:27]=[C:26]([Cl:28])[CH:25]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cc(Cl)cc(Cl)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3,5-dichloro-phenylboronic acid (61 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=2)=[CH:4][CH:3]=1.[C:21]([N:29]=C=O)(=[O:28])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([NH2:29])=[O:28])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cn1cnc(-c2ccnc(N)c2)c1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: Cn1cnc(-c2ccnc(NC(N)=O)c2)c1-c1ccc(F)cc1
Temperature: 50 °C
Yield: 65.4 %

Procedure:
4-[5-(4-Fluoro-phenyl)-1-methyl-1H-imidazol-4-yl]-pyridin-2-ylamine (72 mg, 0.27 mmol) and benzoyl isocynate (59 mg, 0.40 mmol) are mixed in DCM (2.0 mL). The reaction is sealed and heated at 50° C. for 16 hrs. Then the solvent is removed and to the residue are added ethanol (2.0 mL) and potassium carbonate (56 mg, 0.40 mmol). The mixture is then heated at 80° C. for 35 min. The solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (45 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. The crude is washed with methanol (3×5 mL) and dried to give 55 mg of the titled product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@@H:4]([CH3:6])[NH2:5].[C:8]1([CH2:14][O:15][C:16]([N:18]2[CH:22]([CH2:23][CH2:24][CH:25]=[C:26]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:27]([O:29][CH3:30])=[O:28])[C:21](=O)[O:20]C2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:1][O:2][C:3](=[O:7])[C@@H:4]([CH3:6])[NH:5][C:21](=[O:20])[C@H:22]([CH2:23][CH2:24]/[CH:25]=[C:26](/[C:27]([O:29][CH3:30])=[O:28])\[NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[NH:18][C:16]([O:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:17]
Reactant: COC(=O)C(=CCCC1C(=O)OCN1C(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](C)N
Product: COC(=O)/C(=C/CC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C)C(=O)OC)NC(=O)OC(C)(C)C
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
A mixture of 3.3 g of D-alanine methyl ester and 7.1 g of 46c is heated at 140° C. for 10 min, then another 1.6 g of D-alanine methyl ester is added. Heating is continued at 140° C. for an additional 10 min. After cooling to ambient temperature the crude product is chromatographed on silica gel using variable gradient hexane/ethyl acetate. Purified product (6.7 g) is recovered. The material is crystallized from hexanes-ether to give 5.8 g of the desired product 47c as a solid. NMR δ 1.43(s,d,12H); 1.80-2.10(m,2H); 2.23-2.36(m,2H); 3.72(s,3H); 3.76(s, 3H); 4.15-4.27 (m,1H); 4.50-4.60 (m,1H); 5.11(b s,2H); 5.76(b s,1H); 6.38(b s,1H); 6.47(b t,1H); 6.81(b s,1H); 7.34(m,5H); 13C-NMR: 17.82 (--CHCH3 ; 24.33(--CH2 --CH2); 28.02(C(CH3)3); 30.99(--CH2CH=C); 47.94(--CHCH3); 52.17 (--OCH3); 52.29(--OCH3); 54.28(OCCHNH); 66.93(--CH2Ar); 80.43(--OC(CH3)3); 126.57(--HNC=C); 127.86(phenyl ring carbon); 127.94 (phenyl ring carbon); 128.12(phenyl ring carbon); 128.28(phenyl ring carbon); 135.98(phenyl ring carbon); 153.45(OCONH); 156.21(OCONH--); 165.13(--CONH--); 171.04(--CO2 --); 172.99(--CO2 --). IR(KBr, cm-1) 3300(s); 1720(s); 1690(s); 1650(s); 1510(s); MS(CI) m/z 522(MH)+ ; 466(MH--C4H8)+ ; 422(MH--C4H8CO2)+. MS(FAB) m/z 544(M+Na)+ ; 522MH+ ; 466(MH--C4H8)+ ; Anal Calcd: C, 57.57; H, 6.76; N, 8.06; Found: C, 56.98; H 6.66; N, 7.88. [α]D26 -7±1; m.p. 120°-121° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[OH-].[K+].Cl>O.CO>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCCCCCOc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCCCCCCOc1ccc(C(=O)O)cc1
Yield: 86.2 %

Procedure:
4.9 g of compound (8) and 3.7 g of potassium hydroxide were added to a solvent mixture of 50 ml of water and 20 ml of methanol, and the mixture was refluxed for 5 hours. The reaction solution was poured to 200 ml water, and the mixture was adjusted approximately to pH 1 with concentrated hydrochloric acid. The solid matters formed therein were filtered, washed with water and dried, to obtain 4.0 g of compound (9) (Yield: 87%)
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[S:11]([N:14]1[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH:15]1[CH2:21][C:22]([O:24]CC)=[O:23])(=[O:13])=[O:12]>CO.O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[S:11]([N:14]1[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH:15]1[CH2:21][C:22]([OH:24])=[O:23])(=[O:13])=[O:12]
Reactant: CCOC(=O)CC1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1Cl
Reaction time: 16 h

Procedure:
Lithium hydroxide (0.92 mg, 21.9 mmol) was added to a cooled solution of ethyl 2-(1-(2,4-dichlorophenylsulfonyl)-3-oxopiperazin-2-yl)acetate (2.7 g, 7.3 mmol) in methanol (25 ml) and water (6 ml), and stirring was carried out for 16 h at room temperature (TLC monitoring). The solvent was removed using a rotary evaporator and the residue was taken up in water. The aqueous phase was washed with diethyl ether and acidified with HCl, and the product was extracted with ethyl acetate. The organic phase was then washed with saturated NaCl solution. The organic phase was dried over sodium sulfate and concentrated to dryness.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14](=[CH2:15])[C:13](=[O:16])[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([SH:39])[CH:35]=[CH:36][C:37]=1[F:38].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:14]([CH2:15][S:39][C:34]2[CH:35]=[CH:36][C:37]([F:38])=[C:32]([F:31])[CH:33]=2)[C:13](=[O:16])[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C1C(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@]1(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Fc1ccc(S)cc1F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2C(=O)[C@H]1CSc1ccc(F)c(F)c1
Temperature: 80 °C
Yield: 141 %

Procedure:
A suspension of di-tert-butyl (1S,2R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-methylidene-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate (350.00 g, 826.43 mmol) in toluene (2.95 L) is treated with 3,4-difluorobenzenethiol (172.49 g, 1.18 mol) and triethylamine (205.61 mL, 149.28 g, 1.48 mol) at 25° C. The mixture is stirred at 80° C. After twelve hours, the reaction was cooled to room temperature, washed sequentially with 2N aqueous NaOH (pH=10) and aqueous. 1N HCl (pH=4), dried over MgSO4, and concentrated in vacuo to yield a residue. Triturate the residue with hexane (1 L) and remove the solvent to yield the title compound (664 g, 100% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[F:44][C:45]1[CH:62]=[CH:61][C:48]([CH2:49][C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53](=[O:60])[NH:52][N:51]=2)=[CH:47][C:46]=1[C:63]([N:65]1[CH2:70][CH2:69][CH:68](O)[CH2:67][CH2:66]1)=[O:64]>C(Cl)Cl>[F:44][C:45]1[CH:62]=[CH:61][C:48]([CH2:49][C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53](=[O:60])[NH:52][N:51]=2)=[CH:47][C:46]=1[C:63]([N:65]1[CH2:66][CH2:67][CH:68]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[CH2:69][CH2:70]1)=[O:64]
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(O)CC1
Reactant: Cc1cccc(O)n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc(OC2CCN(C(=O)c3cc(Cc4n[nH]c(=O)c5ccccc45)ccc3F)CC2)n1
Temperature: 20 °C
Reaction time: 4 h
Yield: 7.3 %

Procedure:
6-methylpyridin-2-ol (95 mg, 0.87 mmol) was added in one portion to polymer supported triphenylphosphine (1.89 mmol/g; 460 mg, 0.87 mmol) in DCM (5 ml). Di-tert-butyl azodicarboxylate (201 mg, 0.87 mmol) and 4-(4-fluoro-3-(4-hydroxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (2a) (111 mg, 0.29 mmol) in DCM (1 ml) was added and the resulting mixture was stirred at 20° C. for 4 hours. The reaction mixture was diluted with DCM and washed with water (×2). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XTerra C18 column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (10 mg, 7.3% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.70-1.80 (1H, m), 1.85-1.95 (2H, m), 2.02-2.08 (1H, m), 2.41 (3H, s), 3.22-3.28 (1H, m), 3.51-3.57 (1H, m), 3.74-3.83 (1H, m), 3.95-4.03 (1H, m), 4.28 (2H, s), 5.32-5.35 (1H, m), 6.50 (1H, d), 6.69 (1H, d), 7.02 (1H, t), 7.26-7.29 (1H, m), 7.33-7.35 (1H, m), 7.44 (1H, t), 7.71-7.79 (3H, m), 8.45-8.48 (1H, m), 10.33 (1H, s); m/z (LC-MS, ESI+), RT=2.26 (M+H 473.6).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:24][N:25]([CH3:36])[CH2:26][CH2:27][NH:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[CH3:24][N:25]([CH3:36])[CH2:26][CH2:27][NH:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:31][CH:30]=1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN(C)CCNc1ccc(N)cc1
Product: CN(C)CCNc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(2-dimethylamino-ethylamino)-aniline.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2/[C:11](=[CH:19]/[C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)/[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>C(Cl)(Cl)Cl>[O:18]=[C:12]1[NH:13][C:14]2[C:10](/[C:11]/1=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[C:9]([C:5]1[CH:4]=[C:3]([NH:2][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([F:32])=[CH:34][CH:35]=3)[CH:8]=[CH:7][CH:6]=1)[CH:17]=[CH:16][CH:15]=2
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1Nc2cccc(-c3cccc(NC(=O)c4ccc(F)cc4)c3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one hydrochloride (25 mg, 0.074 mmol) (from Example 5 supra) and Et3N (21 μL , 0.148 mmol) in 3 mL of chloroform was treated with 4-fluorobenzoyl chloride (10.5 μL , 0.088 mmol) (Aldrich). The resulting reaction mixture was stirred at room temperature for 8 h and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 50% ethyl acetate-hexanes elution) to provide pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenyl]-4-fluorobenzamide (yield: 26 mg, 83%) as a yellow solid (mp 130-131° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:49][C:50]1[S:51][C:52]([O:58][C:59]2[CH:66]=[CH:65][C:62]([C:63]#[N:64])=[CH:61][CH:60]=2)=[C:53]([CH:55]2[CH2:57][CH2:56]2)[N:54]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]([C:13](=[O:15])[NH:49][C:50]1[S:51][C:52]([O:58][C:59]2[CH:66]=[CH:65][C:62]([C:63]#[N:64])=[CH:61][CH:60]=2)=[C:53]([CH:55]2[CH2:57][CH2:56]2)[N:54]=1)([CH3:17])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: N#Cc1ccc(Oc2sc(N)nc2C2CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1nc(C2CC2)c(Oc2ccc(C#N)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-Benzyloxycarbonylamino-2-methyl-propionic acid (360 mg, 1.52 mmol), HBTU (576 mg, 1.52 mmol) and Et3N (0.21 mL, 1.5 mmol) in DMF (4 mL) was stirred at room temperature for 30 min. To this was added a solution of 4-(2-Amino-4-cyclopropyl-thiazol-5-yloxy)-benzonitrile (260 mg, 1.01 mmol) in DMF (4 mL). The mixture was heated at 85° C. for 18 h and partitioned between EtOAc and 3M HCl. The organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound. m/z 477.1 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]2[S:13][CH:14]=[CH:15][C:10]2=[CH:9][C:8]=1[CH:16]([N:18]1C(=O)C2C(=CC=CC=2)C1=O)[CH3:17].O.NN>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]2[S:13][CH:14]=[CH:15][C:10]2=[CH:9][C:8]=1[CH:16]([NH2:18])[CH3:17]
Reactant: CC(c1cc2ccsc2nc1-c1ccccn1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(N)c1cc2ccsc2nc1-c1ccccn1
Temperature: 60 °C
Yield: 92.1 %

Procedure:
2-(1-(6-(Pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione (220 mg, 0.57 mmol) was slurried in ethanol (5 mL). To this slurry was added hydrazine hydrate (500 uL, 10.3 mmol, 18 eq). The reaction was heated to 60° C. for 2 h, then cooled to rt and filtered. The filtrate was concentrated and redissolved in ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford 1-(6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)-ethanamine (134 mg, 91.9% yield). 1H NMR (400 MHz, CDCl3) δ 8.69 (ddd, J=4.7, 1.6, 0.8 Hz, 1H), 8.39 (s, 1H), 7.87 (m, 2H), 7.57 (d, J=5.9 Hz, 1H), 7.34 (ddd, J=6.8, 5.1, 2.0, 1H), 7.31 (d, J=5.9 Hz, 1H), 4.63 (q, J=6.7 hz, 1H), 1.44 (d, J=6.7 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[NH2:29]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([NH:29][C:28]3[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:26]([O:25][CH3:24])[CH:27]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(Nc3cc(OC)c(OC)c(OC)c3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (150.0 mg, 0.459 mmol) and 3,4,5-trimethoxy aniline were reacted as starting materials at 140° C. for 5 hours and post treatment was then conducted, whereby the title compound was obtained as a pale yellow crystalline powder (155.0 mg, 71.3%). Melting point: 125.4-126.3° C. (chloroform-hexane).
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[Br:16][C:17]1[C:22]2[NH:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([O:27][CH3:28])[CH:18]=1>>[Br:16][C:17]1[C:22]2[N:23]([C:2]3[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=3)[CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([O:27][CH3:28])[CH:18]=1
Reactant: CC[C@H](COC)n1cc(Br)nc(Br)c1=O
Reactant: COc1cc(Br)c2c(c1)OCCN2
Product: CC[C@H](COC)n1cc(Br)nc(N2CCOc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 556 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. 1H NMR (300 MHz, CDCl3): δ 7.14 (s, 1H), 6.75 (d, J=2.5 Hz, 1H), 6.46 (d, J=2.5 Hz, 1H), 5.08-4.86 (m, 1H), 4.50-3.88 (m, 4H), 3.77 (s, 3H), 3.70-3.52 (m, 2H), 3.36 (s, 3H), 1.92-1.70 (m, 2H), 0.93 (t, J=7.5 Hz, 3H); HRMS (ESI) m/z 501.9992 [(M+H)+, calcd for C18H22N3O4Br2 501.9977].
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[OH:5][C:6]1[CH:15]=[C:14]([I:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[I:16][C:14]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:5][CH:2]([CH3:4])[CH3:3])[CH:15]=1
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(I)cc1OC(C)C
Yield: 98.3 %

Procedure:
2-Iodopropane (6.42 g) was added at room temperature to a mixture of methyl 2-hydroxy-4-iodobenzoate (7.00 g), potassium carbonate (6.96 g), and DMF (100 mL), and the resultant mixture was stirred at 70 C for 2 days in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (7.92 g)
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[NH2:13][C:14]1[C:15]([I:28])=[C:16]([C:25]([Cl:27])=[O:26])[C:17]([I:24])=[C:18]([C:22]=1[I:23])[C:19]([Cl:21])=[O:20]>C1C=CC=CC=1.CC(C)=O>[C:1]([NH:13][C:14]1[C:22]([I:23])=[C:18]([C:19]([Cl:21])=[O:20])[C:17]([I:24])=[C:16]([C:15]=1[I:28])[C:25]([Cl:27])=[O:26])(=[O:3])[CH3:2]
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reaction time: 1 h

Procedure:
A mixture of 50 ml. of acetic anhydride and 0.1 ml. of conc. sulfuric acid was stirred at room temperature for 5 minutes. To this mixture was added 15 g. (0.025 mole) of 5-amino-2,4,6-triiodoisophthaloyl chloride in one portion and stirring was continued at room temperature for one hour. The mixture was stored overnight at 0°. Filtration furnished 16 g. of solid material. The product was recrystallized from ethyl acetate to furnish 10 g. (63%) of pure product. The compound was shown to be pure by tlc (silica plate-benzene/acetone 80/20).