Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[Cl:29][CH2:30][C:31](Cl)=[O:32]>C1COCC1>[Cl:29][CH2:30][C:31]([NH:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20])=[O:32]
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.08 h
Yield: 77 %

Procedure:
Triethylamine (0.7 g, 6.5 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.8 g, 2.6 mmol) in THF (50 mL). After stirring for 5 minutes, chloroacetyl chloride (0.4 g, 3.6 mmol) was added slowly. The resulting brown suspension was refluxed overnight. The mixture was cooled and quenched with methanol (1 mL). The mixture was concentrated, and the solid was stirred with 0.5N HCl (30 mL). The mixture was filtered, and the solid was slurried with ethanol (15 mL) to give 2-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.7 g, 76%): 1H NMR (DMSO-d6) δ 1.99-2.04 (m, 1H), 2.35-2.65 (m, 2H), 2.85-2.94 (m, 1H), 4.19 (s, 2H, CH2), 5.10-5.18 (dd, J=5.1 and 13.3 Hz, 1H, CH), 7.50-7.66 (m, 3H), 8.80 (t, J=5.7 Hz, 1H, NH), 11.01 (s, 1H, NH).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@:15]([OH:29])([CH2:16][C@@H:17]([OH:28])[CH2:18][C@@H:19]2[OH:27])[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@:15]([OH:29])([CH2:16][C@@H:17]([O:28][C:30](=[O:32])[CH3:31])[CH2:18][C@@H:19]2[OH:27])[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC(C1OCCO1)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]4(O)C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@H](O)[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)C5OCCO5)CC[C@H]4[C@@H]3C=C[C@@]2(O)C1
Temperature: 0 °C

Procedure:
In 5 ml of pyridine was dissolved 400 mg of 20-(1,3-dioxolan-2-yl)pregn-6-ene-1α,3β,5α-triol. To this solution was added 0.11 ml of acetic anhydride at a temperature of -10°-0° C. and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture thus obtained was poured in ice-water and stirred at room temperature for 30 minutes. This mixture was then extracted with ether and the extracts were pooled, washed successively with water, cold diluted hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution and dried over magnesium sulfate, followed by concentration under reduced pressure. Finally the concentrate was purified by silica gel chromatography to give 420 mg of 20-(1,3-dioxolan-2-yl)-3β-acetoxypregn-6-ene-1α,5α-diol showing the following properties.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[F:14].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>ClCCl>[CH3:26][S:27]([O:13][CH2:12][C:9]1[CH:10]=[N:11][C:6]([O:5][C:4]2[CH:15]=[CH:16][C:17]([F:18])=[C:2]([F:1])[CH:3]=2)=[C:7]([F:14])[CH:8]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cnc(Oc2ccc(F)c(F)c2)c(F)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cnc(Oc2ccc(F)c(F)c2)c(F)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of (6-(3,4-difluorophenoxy)-5-fluoropyridin-3-yl)methanol (8.4 g, 26.7 mmol) and triethylamine (6.89 mL, 49.4 mmol) in dichloromethane (DCM) (100 mL) was added methanesulfonyl chloride (4.8 g, 41.9 mmol). The reaction mixture was stirred at 20° C. for 2 hr. then 200 mL of H2O was added. The organic layer was separated, dried over Na2SO4, and then concentrated under reduced pressure to give (6-(3,4-difluorophenoxy)-5-fluoro pyridin-3-yl)methyl methanesulfonate (8 g, 42.3%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]1)[CH:3]=[C:2]2[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: C1COCCN1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCOCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and morpholine. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CDCl3) δ ppm 8.06 (d, J=8.0 Hz, 1 H), 7.62-7.53 (m, 4 H), 7.40 (t, J=7.6 Hz, 1 H), 7.32 (d, J=7.6 Hz, 1 H), 6.42 (s, 1 H), 5.51 (s, 2 H), 4.60 (brs, 2 H), 4.00 (t, J=4.4 Hz, 4 H), 3.59 (s, 2 H), 3.10 (m, 4 H), 2.44 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][C@@H:11]([CH3:14])[CH2:12][OH:13].[BH4-].[Na+]>C(O)C.CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C[C@H](N)CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: C[C@@H](CO)NCc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-Chloro-benzaldehyde (1.4 g, 0.01 mol) was dissolved in dry ethanol (30 mL) and (S)-(+)-2-amino-1-propanol (0.75 g, 0.01 mol) was added. The reaction mixture was stirred overnight at 60° C. The ethanol was evaporated under reduced pressure to give a colorless oil. The oil was then dissolved in dry methanol (30 mL) and cooled in ice. NaBH4 (0.57 g, 0.015 mol) was added slowly in portions, and the resulting solution was left overnight at room temperature. The solvent was evaporated in vacuo, and the residue was dissolved in water, and extracted with CH2Cl2 (3×20 mL). The organic layers were combined and dried with Na2SO4, filtered and evaporated in vacuo to give colorless oily residue, which was purified by column chromatography (silica gel, CH2Cl2:MeOH, 9:1) to afford colorless oil (III-1, 1.85 g, 93%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[C:34]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)(=[O:37])[CH2:35][CH3:36]
Reactant: CCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCCNC4)c[nH]c23)cc1F
Agent: Cl
Product: CCC(=O)N1CCC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A167) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([NH2:11])[C:8]([NH2:10])=[CH:9][C:4]=2[O:3][CH2:2]1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](=O)[C:18](O)=[O:19]>>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[C:18](=[O:19])[NH:10][C:8]2[CH:9]=[C:4]3[O:3][CH2:2][O:1][C:5]3=[CH:6][C:7]=2[N:11]=1
Reactant: Nc1cc2c(cc1N)OCO2
Reactant: O=C(O)C(=O)c1cccs1
Product: O=c1[nH]c2cc3c(cc2nc1-c1cccs1)OCO3

Procedure:
The quinoxalin-2-one of the present example is prepared with Benzo[1,3]dioxole-5,6-diamine and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 7-thiophen-2-yl-5H-1,3-dioxa-5,8-diaza-cyclopenta[b]naphthalen-6-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:13][C:14]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([OH:22])[CH:21]=1)=[O:15].[OH-].[K+].Cl>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:13][C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([OH:22])[CH:21]=2)=[O:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC(=O)c1cccc(O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C=CC(=O)c2cccc(O)c2)cc1OC
Temperature: 0 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
A solution of 3,4-Dimethoxybenzaldehyde (16.6 g, 100 mmol) in EtOH (75 mL) was treated with 3-Hydroxyacetophenone (13.6 g, 100 mmol) and the resulting solution cooled to 0° C. in an ice bath. A 200 mL solution of aqueous KOH (28 g, 500 mmol) was added slowly and the resulting bright red solution was allowed to stir overnight (16 h) at room temperature. The mixture was then acidified to pH 5 by the dropwise addition of concentrated HCl and the resulting suspension extracted with EtOAc (2×200 mL). The combined organic extract was washed with a saturated NaCl solution (2×100 mL), dried over MgSO4, filtered, evaporated, and flash chromatographed (silica gel, 30% 50% EtOAc/hexanes) to give crude material. The crude solid was crystallized from EtOAc to afford 13.9 g (49%) of a yellow colored solids: IR (neat) 3420, 1650, 1575, 1510, 1265, 1140 cm−1; 1H NMR (CDCl3, 300 MHz) 7.80 (d, J=15.6 Hz, 1H), 7.68 (s, 1H), 7.59, (d, J=7.7 Hz, 1H), 7.42-7.36 (m, 2H), 7.24 (dd, J=8.3, 1.8 Hz, 1H), 7.16-7.13 (m, 2H), 6.90 (d, J=8.3 Hz, 1H), 6.82 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H); 13C NMR (CDCl3, 75 MHz) 191.3, 157.0, 152.0, 149.7, 146.1, 140.1, 130.2, 128.2, 123.8, 121.2, 120.7, 120.3, 115.7, 111.6, 110.7, 56.4.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[C:5](Cl)(=[O:9])[C:6]([Cl:8])=[O:7].Cl>>[Cl:8][C:6](=[O:7])[C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[O:9]
Reactant: CC(C)O
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Product: CC(C)OC(=O)C(=O)Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
The propan-2-ol (38.2 mL, 499 mmol) was added drop wise over 15 min to a cold (0° C.), nitrogen purged solution of oxalyl dichloride (101 g, 799 mmol) and the reaction was stirred at room temperature for 2.5 h. Then a reflux condenser was fitted and a slight vacuum was applied for about 1 h until HCl gas was removed (the HCl was trapped in by a sat'd solution of NaHCO3). The reflux condenser was removed and the flask was fitted with a short path distillation head. Excess reagent was removed by distillation under house vacuum (oil bath heated to 65° C.), and then the temperature was raised to between 85-95° C. and the product was distilled (NOTE: The 1st fraction of ˜5 mL was discarded) to provide isopropyl 2-chloro-2-oxoacetate 52.62 g (70%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[O:23][CH:24]=[CH:25][C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C>[OH:29][CH:28]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[O:23][CH:24]=[CH:25][C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 72.1 %

Procedure:
3-Methyl-furan-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.200 g, 3.33 mmol) and ethyl formate (0.8 mL, 9.95 mmol) were dissolved in anhydrous ethanol (30 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (6.2 mL, 16.63 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a light yellow precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure 3-Methyl-furan-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.931 g, 2.4 mmol, 72%).
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]([C:19]([O:21][CH3:22])=[O:20])=[C:11]([CH3:23])[N:10]=1)C1C=CC=CC=1.C1COCC1.[H][H]>[C].[Pd].C(O)C>[OH:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]([C:19]([O:21][CH3:22])=[O:20])=[C:11]([CH3:23])[N:10]=1
Reactant: COC(=O)c1cc(C(=O)OC)c(OCc2ccccc2)nc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)OC)c(O)nc1C
Yield: 48.2 %

Procedure:
A mixture of dimethyl 2-(benzyloxy)-6-methylpyridine-3,5-dicarboxylate (14.4 g), 10% palladium carbon (containing 55% water, 9.00 g), THF (20 mL), and ethanol (20 mL) was stirred at room temperature for 1 hour in a hydrogen atmosphere. The catalyst was filtered off, and then, the obtained filtrate was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to obtain the title compound (4.96 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:2].F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:15])[NH:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCOC(=O)NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)NCCc1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 85 °C
Yield: 119.5 %

Procedure:
Combine 6.2 mmol of [2-(4-hydroxy-phenyl)-ethyl]-carbamic acid ethyl ester (3.6.0 g, 17.2 mmol), 4-fluorobenzonitrile (2.1 g, 17.2 mmol), cesium carbonate (11.2 g, 34.4 mmol), and N,N-dimethylformamide (80 mL), stir and heat at 85° C. for 18 hours. Cool to room temperature and evaporate on a rotary evaporator, took up residue in brine then extracted with ethyl acetate (3×50 mL). Dry the combined ethyl acetate extracts over sodium chloride/magnesium sulfate, filter, and concentrate on a rotary evaporator to yield the crude product (4.5 g). The crude product is purified by flash column chromatography on silica gel eluting with ethyl acetate and hexanes to yield {2-[4-(4-cyano-phenoxy)-phenyl]-ethyl}-carbamic acid ethyl ester (2.3 g): 1H NMR (CDCl3, 300.00 MHz): 7.66-7.60 (m, 2H), 7.31-7.24 (m, 2H), 7.07-7.00 (m, 4H), 4.72 (s, 1H), 4.16 (q, 2H, J=7.0 Hz), 3.48 (q, 2H, J=6.7 Hz), 2.86 (t, 2H, J=7.0 Hz), 1.27 (t, 3H, J=7.0 Hz).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])[CH3:3].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1>>[C:2]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([N:21]1[CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20]1)=[O:19])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: c1ccc2c(c1)CNC2
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1Cc2ccccc2C1

Procedure:
N-t-Boc-L-phenylalanine (1 mmol) and isoindoline (J. Org. Chem. 1988, 53, p5382, 70-80% purity, 1 mmol) were coupled according to Procedure A and the product purified by chromatography on silica gel eluted with 20% and 50% ethyl acetate-hexanes giving an amber oil (88 mg, 23%): TSPMS 367 (MH+, 100%).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=1.[N:11]1([CH2:15][C:16]([CH3:26])([O:18][C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=2)[CH3:17])[CH2:14][CH2:13][CH2:12]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:11]1([CH2:15][C:16]([CH3:26])([CH3:17])[O:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:2]3[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=3)=[N:23][CH:24]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)(CN1CCC1)Oc1ccc(N)nc1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc(Nc2ccc(OC(C)(C)CN3CCC3)cn2)c1=O
Temperature: 90 °C
Reaction time: 18 h

Procedure:
4-Bromo-6-chloro-2-methylpyridazin-3(2H)-one (2.18 g, 9.75 mmol, Eq: 1.30), 5-(1-(azetidin-1-yl)-2-methylpropan-2-yloxy)pyridin-2-amine (1.66 g, 7.5 mmol, Eq: 1.00), Xantphos (651 mg, 1.13 mmol, 0.15 equiv) and Cs2CO3 (8.55 g, 26.3 mmol, 3.5 equiv) were combined in dioxane and the reaction mixture was degassed under vacuum with argon displacement. To the solution was added the Pd2(dba)3 (515 mg, 563 μM, 0.075 equiv) and the mixture was degassed again with argon. The reaction mixture was stirred under argon at 90° C. for 18 hrs before cooling to ambient temperature. The reaction mixture was filtered through a plug of celite. The celite cake was washed with THF and dichloromethane. The combined filtrate and washes were concentrated in vacuo. The crude product was purified by Analogix MPLC (60 g column; elute with 0.5% to 15% MeOH/DCM) to afford the desired product (1.43 g) as a tan solid. (M+H)+=364 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 (s, 6 H) 2.12 (quin, J=7.08 Hz, 2 H) 2.59 (s, 2 H) 3.35 (t, J=6.99 Hz, 4 H) 3.81 (s, 3 H) 6.83 (d, J=8.69 Hz, 1 H) 7.32 (dd, J=8.88, 2.83 Hz, 1 H) 8.09 (d, J=3.02 Hz, 1 H) 8.18 (s, 1 H) 8.25 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:5]([O:7][CH3:8])=[O:6].[C:22](OCC)(=[O:28])[C:23](OCC)=[O:24]>CCOCC>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:12]2[C:11]3[C:2](=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=3)[NH:1][C:23](=[O:24])[C:22]2=[O:28])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: COC(=O)c1ccc(NCc2ccc(OC)cc2)c(N)c1
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)c(=O)n2Cc1ccc(OC)cc1
Reaction time: 3 h
Yield: 74 %

Procedure:
A mixture of methyl 3-amino-4-(4-methoxybenzylamino)benzoate (3 g, 10.48 mmol) and diethyl oxalate (100 ml) was stirred for 3 h at reflux and then cooled with a water/ice bath, and diluted with ether (500 ml). Tthe product was collected by filtration to afford methyl 1-(4-methoxybenzyl)-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate as a green solid (2.64 g, 74%).
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C1C2C(COC([NH:62][C@H:63]([C:67](O)=[O:68])[CH:64]([CH3:66])[CH3:65])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:62][C@H:63]([C:67]([O:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:68])[CH:64]([CH3:66])[CH3:65]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)[C@H](N)C(=O)O[C@H]1c2ccccc2C[C@]1(Cc1ccc(C(=O)O)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.3 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (230 mg, 0.60 mmol), DCC (148 mg, 0.72 mmol) and DMAP (7 mg, 0.059 mmol) in ethyl acetate (12 mL), was added N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valine (193 mg, 0.60 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (250 mg) was dissolved in dry THF (7 mL) and cooled to 0° C. Dimethylamine (7 mL, 20% in THF) was added drop wise at N2 atmosphere and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 105 mg (36%) of the title compound as an off white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:26][N:27]1[C:32]2[N:33]=[CH:34][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:36][C:31]=2[CH2:30][O:29][C:28]1=[O:46]>>[CH:20]([N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:35]5[CH:34]=[N:33][C:32]6[N:27]([CH3:26])[C:28](=[O:46])[O:29][CH2:30][C:31]=6[CH:36]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:25])[C:13]2=[O:24])[C:16]([CH3:23])=[N:17]1)([CH3:22])[CH3:21]
Reactant: CN1C(=O)OCc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5c(c4)COC(=O)N5C)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 0.125 mmol) and 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dihydro-pyrido[2,3-d][1,3]oxazin-2-one (Stage 170.1.1) to give the title compound as a beige solid. (HPLC: tR 2.59 min (Method A); M+H=484 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.35-8.33 (m, 1H), 8.21 (s, 1H), 8.15-8.11 (m, 1H), 7.91-7.83 (m, 2H), 7.52-7.49 (m, 1H), 5.36-5.29 (m, 2H), 4.56 (qt, 1H), 3.58 (s, 3H), 3.35 (s, 3H), 1.95 (s, 3H), 1.46 (d, 6H))
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[CH3:31][N:32]1C=CN=C1>[Fe-4](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].[K+].[Cu]I>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:31]#[N:32])=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: Cn1ccnc1
Agent: N#C[Fe-4](C#N)(C#N)(C#N)(C#N)C#N
Agent: [Cu]I
Agent: [K+]
Product: COc1cccc(-c2c(C#N)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Yield: 31.5 %

Procedure:
A mixture of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (85 mg, 0.162 mmol) (Example 33), potassium ferrocyanide (13.71 mg, 0.032 mmol), copper(I) iodide (3.09 mg, 0.016 mmol) in 1-methylimidazole (1 mL, 12.55 mmol) was subjected to microwave reaction at 160° C. for 1 h. Purification by chromatography on silica gel, eluting with a gradient of 40-60% ethyl acetate in cyclohexane, afforded the title compound (24 mg). LCMS (A) m/z: 470 [M+1]+, Rt 1.58 min (acidic), Rt 1.09 min (basic).