Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[CH:4]=1)=[O:2].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:18][CH3:19])=[O:8])=[C:5]([CH3:12])[CH:4]=1)=[O:2]
Reactant: CCO
Reactant: Cc1cc(C=O)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(C=O)cc1C
Temperature: 80 °C
Yield: 80 %

Procedure:
To a stirred solution of 4-formyl-2-methylbenzoic acid (3 g, 18.2 mmol) in ethyl alcohol (EtOH; 30 mL) was added sulfuric acid (H2SO4, x M; 2 mL), and the reaction mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with H2O. The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a solid (2.8 g, 80%): 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.04 (m, 1H), 7.75 (m, 2H), 4.43 (m, 2H), 2.65 (s, 3H), 1.42 (m, 3H).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]#[C:13][CH2:14]O)[C:8]=2[C:16]([F:19])([F:18])[F:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]P(Br)Br>ClCCl>[Br:20][CH2:14][C:13]#[C:12][C:9]1[C:8]([C:16]([F:19])([F:18])[F:17])=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:11][N:10]=1
Reactant: BrP(Br)Br
Reactant: OCC#Cc1noc(-c2ccccc2)c1C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1c(C#CCBr)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38 %

Procedure:
To a solution of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)prop-2-yn-1-ol (Preparation 62B, 0.465 g, 1.740 mmol) in dichloromethane (9.0 mL) at 0° C. was added a 1.0 M solution of tribromophosphine in dichloromethane (2.09 mL, 2.09 mmol). After 5 min., the ice-bath was removed, and the reaction mixture was stirred at room temperature overnight. HPLC and LCMS analysis indicated that there was still significant starting material remaining. Additional tribromophosphine (1.0 M in dichloromethane) (2.09 mL, 2.09 mmol) was added, and the reaction mixture was stirred at room temperature for 4.5 h. Additional tribromophosphine (1.0 M in dichloromethane) (2.09 mL, 2.09 mmol) was added, and the reaction mixture was stirred at room temperature over the weekend. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. Concentration under reduced pressure provided the crude product, which was loaded with a minimum amount of dichloromethane on a fitted funnel containing a layer of Celite topped with a layer of silica gel. The plug column was eluted with a mixture of ethyl acetate and hexane (1%-3%) to give 3-(3-bromoprop-1-ynyl)-5-phenyl-4-(trifluoromethyl)isoxazole (0.219 g, 0.663 mmol, 38% yield) as a clear, colorless oil. The product had an HPLC ret. time=2.95 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=331.93.
Reaction SMILES: C(OC(=O)C([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:25])[NH2:24])[CH:18]=2)=[O:15])=[N:10][CH:9]=1)C)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=[C:45]([CH2:47][C:48]([OH:50])=[O:49])N=2)CCCC1.C1(CNC2C=C(C=CC=2)C(N)=O)CCCC1.C(OC(=O)C(SC1SC(N)=NC=1)C)C>>[C:23]([C:19]1[CH:18]=[C:17]([N:16]([CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:45][CH2:47][C:48]([OH:50])=[O:49])=[CH:9][N:10]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:25])[NH2:24]
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(N)=O)c2)s1
Agent: CCOC(=O)C(C)Sc1cnc(N)s1
Agent: NC(=O)c1cccc(NCC2CCCC2)c1
Product: NC(=O)c1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-carbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3-(cyclopentylmethyl-amino)-benzamide and (2-amino-thiazol-5-ylsulfanyl) propionic acid ethyl ester
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9](=O)[NH:10][N:11]=[CH:12][C:13]=2[N:14]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:9]1[C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:2]=3[F:1])=[N:14][C:13]=2[CH:12]=[N:11][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ncc2nc(Oc3ccc(F)cc3F)ccc12
Product: Fc1ccc(Oc2ccc3c(Cl)nncc3n2)c(F)c1
Temperature: 95 °C

Procedure:
A mixture of 2-(2,4-difluorophenoxy)pyrido[3,2-d]pyridazin-5(6H)-one (1.00 g, 3.63 mmol) in POCl3 (8.00 mL, 85.82 mmol) was heated at 95° C. for 4 h. The excess POCl3 was removed under reduced pressure and the crude residue was treated with ice and 1N NaOH. The precipitated solid was filtered, rinsed with 2×5 mL of water followed by 2×5 mL of ether to provide 5-chloro-2-(2,4-difluorophenoxy)pyrido[3,2-d]pyridazine as a tan amorphous solid. MS (ESI, pos.ion) m/z: M+1=294.0
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]/[C:9](=[CH:14]\[C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:27])(=[O:26])[N:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:23](=[O:32])[CH2:22]2)=[C:17]([F:33])[CH:16]=1)/[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[B-](F)(F)(F)F.COC1C([P@](CC[P@](C2C=CC=CC=2)C2C(OC)=CC=CC=2)C2C=CC=CC=2)=CC=CC=1.C1CC=CCCC=C1.[Rh]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:26])(=[O:27])[N:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:23](=[O:32])[CH2:22]2)=[C:17]([F:33])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C(=C/c1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)c(F)c1)NC(=O)OC(C)(C)C
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: COc1ccccc1[P@](CC[P@](c1ccccc1)c1ccccc1OC)c1ccccc1
Solvent: CCO
Solvent: C1=CCCC=CCC1
Product: COC(=O)[C@H](Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)c(F)c1)NC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
Methyl (2Z)-2-[(tert-butoxycarbonyl)amino]-3-[4-(2-tert-butyl-1,1-dioxido-3-oxoisothiazolidin-5-yl)-3-fluorophenyl]acrylate (1.24 g, 2.56 mmol) in ethanol (100 mL) was degassed and (R,R)-(−)-1,2-bis[(o-methoxyphenyl)(phenyl)phosphino]ethane(1,5-cyclooctadiene) rhodium (I) tetrafluroborate (58 mg, 0.077 mmol) was added under nitrogen. The solution was placed under a hydrogen atmosphere (50 psi) and shaken for 16 h. The solution was concentrated in vacuo and purified by silica gel chromatography (10–40% ethyl aceate:hexanes) to afford product as a white foam (1.14 g, 92%). 1H NMR (400 MHz, CDCl3): δ 7.29–7.27 (m, 1H), 7.03–6.95 (m, 2H), 5.06–5.02 (m, 2H), 4.61–4.57 (brs, 1H), 3.73 (s, 3H), 3.31–3.27 (m, 1H), 3.15–3.06 (m, 3H), 1.66 (s, 9H), 1.42 (s, 9H). LCMS found for C22H32FN2NaO7S (M+Na)+: m/z=509.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:10])[CH:6]=[C:7](Cl)Cl)(=[O:3])[CH3:2].[CH3:11][O-:12].[Na+]>CO>[CH3:2][C:1]1[O:3][C:6]([CH2:7][O:12][CH3:11])=[C:5]([CH3:10])[N:4]=1
Reactant: CC(=O)NC(C)C=C(Cl)Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1oc(C)nc1C
Yield: 64.5 %

Procedure:
A solution of 1.8 g of 3-acetamido-1,1-dichlorobut-1-ene and 1,0 g of sodium methylate in 20 ml of methanol is heated at the boiling point under reflux for 24 hours. Thereafter, the methanol is distilled off, the residue is taken up in 5 ml of water and 30 ml of methylene chloride and the organic phase is separated off and distilled in vacuo. 0.9 g of 2,4-dimethyl-5-methoxymethyl-oxazole is obtained, boiling point 54° C./120 mbar.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4].[N+:9]([C:12]1[N:13](CC#C)[CH:14]=[CH:15][N:16]=1)([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N+:9]([C:12]1[N:13]([CH2:2][C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4])[CH:14]=[CH:15][N:16]=1)([O-:11])=[O:10]
Reactant: C#CCNC(=O)CBr
Reactant: C#CCn1ccnc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCNC(=O)Cn1ccnc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 17.6 %

Procedure:
To a round bottom flask was added alkyne 18 (1.56 g, 8.84 mmol), 2-nitroimidazole 10 (1 g, 8.84 mmol) and K2CO3 (1.22 g, 8.84 mmol) in DMF (10 mL). The reaction was stirred overnight. The reaction was diluted with water (100 mL) and the resultant precipitate (1.2 g) was filtered off and washed with water (2×40 mL). The aqueous layer was extracted into EtOAc. The organic layer was concentrated to dryness and combined with the precipitate. The material was purified on a silica gel cartridge using EtOAc:Hex as the eluent to afford a 19 white solid (324 mg, 18%). Mass Spec (lo-res): Calc'd for C8H8N4O3: 208.06; found: 209.10 (M+H).
Reaction SMILES: [CH3:1][C:2]1O[C:4]([CH3:15])=[CH:5][C:6](=[O:14])[C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[NH3:16]>>[CH3:1][C:2]1[NH:16][C:4]([CH3:15])=[CH:5][C:6](=[O:14])[C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: N
Reactant: Cc1cc(=O)c(-c2ccncc2)c(C)o1
Product: Cc1cc(=O)c(-c2ccncc2)c(C)[nH]1

Procedure:
A solution of compound C (8.4 g) in saturated ethanolic ammonia (700 ml) was heated at 120° C. in an autoclave for 67 hours. The solvent was removed by evaporation and the residue recrystallised from ethyl acetate/methanol to give 1,4-dihydro-2,6-dimethyl-4-oxo-3-(4-pyridyl)pyridine (B) (5.1 g) as a brown solid; NMR (d6 -DMSO): 2.1(s,3H), 2.2(s,3H), 6.0(s,1H), 7.2(d,2H), 8.5(broad s,2H), 11.2(broad s,1H); mass spectrum (chemical ionisation, ammonia): 201 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]3)=[CH:2]1.Cl.Cl.Cl.[N:23]1([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][CH:35]([NH:38][C:17]([C:11]3[NH:12][C:13]4[C:9]([CH:10]=3)=[C:8]([O:7][CH2:6][C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:16]=[CH:15][CH:14]=4)=[O:19])[CH2:36][CH2:37]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1cc2c(OCc3ccoc3)cccc2[nH]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCc3ccoc3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid 95 (preparation see below) and amine 5.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](=O)[NH:18][CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:33].CC(O)=O.C1(C)C(C)=CC=CC=1>[Cl-].[Na+].O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]1[NH:18][CH:19]=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:33]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)C1CCCCN1C(=O)OCc1ccccc1)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C(OCc1ccccc1)N1CCCCC1c1nc(-c2ccccc2)c[nH]1
Temperature: 165 °C

Procedure:
2-(2-Oxo-2-phenyl-ethylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (22.83 g, 60 mmol), NH4OAc (ammonium acetate) (63.5 g, 824 mmol), AcOH (acetic acid) (30 mL), and xylene (350 mL) were mixed at room temperature, and with stirring the reaction mixture was warmed in an oil bath at 165° C. for about 6 hours. The reaction mixture was then cooled to room temperature and poured into brine. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to yield 31.24 g of off white powder. This sample was triturated in ethyl ether (100 mL), filtered, and rinsed liberally with ethyl ether to yield 15.12 g (70% over two steps) of the desired product 2-(4-phenyl-1H-imidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester as a white solid. HPLC analysis showed the compound to be 100% pure at 254 nm and 98.1% pure at 214 nm.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8](C(OC(C)(C)C)=O)[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1.[C-:26]#[N:27].[Na+].C(OCC)(=O)C>CS(C)=O>[F:25][C:21]1[CH:20]=[C:19]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][C:26]#[N:27])[CH:4]=3)[NH:8][N:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CCl)ccc21
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CCc1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 8.9 %

Procedure:
To a solution of 1.0 g of tert-butyl 5-(chloromethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate in 5 ml dimethyl sulfoxide was added 204 mg of sodium cyanide, and the mixture was stirred at room temperature for 50 minutes. To the reaction mixture was added 50 ml of ethyl acetate, and after washing with water, the aqueous layer was re-extracted with diethyl ether. The collected organic layer was sequentially washed with water (×2) and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=1:9), and suspended in diethyl ether-diisopropyl ether, to give 62 mg of the title compound as yellow crystals.
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:7][CH:8]1[CH2:12][CH:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[O:10][C:9]1=[O:27])([O:5]C)=[O:4].Cl>CO>[C:3]([CH2:7][C@H:8]1[CH2:12][C@@H:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[O:10][C:9]1=[O:27])([OH:5])=[O:4]
Reactant: COC(=O)CC1CC(CCCCCCc2ccc(Cl)cc2Cl)OC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C[C@H]1C[C@@H](CCCCCCc2ccc(Cl)cc2Cl)OC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 0.1 %

Procedure:
Aqueous NaOH (1M, 1.43 ml, 1.43 mmol) was added slowly to a stirred solution of the diastereoisomers of ±3-(carbomethoxymethyl)-5-[6-(2,4-dichlorophenyl)hexyl]tetrahydrofuran-2-one (185 mg, 0. 478 mmol) in methanol (5 ml) at 0° C. After 5 min at 0° C., the mixture was stirred at room temperature for 6 h, then poured into aqueous HCl and extracted with ether. The solvent was removed under vacuum and the residue heated at 60° C. in a 1:1 mixture of 3M aqueous HCl and tetrahydrofuran for 6 h. The mixture was cooled and extracted with ether. The extracts were washed with water, saturated aqueous NaCl, and dried (MgSO4). The solvent was removed under vacuum to give an oil, which slowly crystallised. The solid was recrystallised (ether/petroleum ether 40°-60° C.) to give the title compound (126 mg, 71%), m.p. 57°-59° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[N+:15]([C:12]1[N:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:26]3[CH:31]=[N:30][C:29]([NH2:32])=[CH:28][CH:27]=3)[CH:7]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)cn1
Temperature: 90 °C
Yield: 89.9 %

Procedure:
A solution of Example A1 (0.525 g, 2.086 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.551 g, 2.504 mmol) in dioxane (16 mL) was sparged with Ar, treated with a solution of K2CO3 (0.577 g, 4.17 mmol) in water (4 mL) and heated at 90° C. for 1 h. The mixture was cooled to RT, treated with water and extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The material was treated with 60% EtOAc/Hex, sonicated and the resulting solid collected via filtration to afford 4-((6-nitropyridin-3-yl)oxy)-[2,3′-bipyridin]-6′-amine (580 mg, 90%) as a dark orange solid. 1H NMR (400 MHz, DMSO-d6): δ 8.66 (d, J=2.5 Hz, 1H), 8.58 (d, J=2.8 Hz, 1H), 8.55 (d, J=5.6 Hz, 1H), 8.40 (dd, J=8.9, 0.5 Hz, 1H), 8.06 (dd, J=8.7, 2.5 Hz, 1H), 7.96 (dd, J=8.9, 2.8 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.02 (dd, J=5.6, 2.3 Hz, 1H), 6.48 (dd, J=8.7, 0.7 Hz, 1H), 6.32 (s, 2H); MS (ESI) m/z: 310.1 (M+H+).
Reaction SMILES: CN(C=O)C.C(Cl)(C([Cl:10])=O)=O.[CH3:12][O:13][C:14]1[C:19]2[C:20]3[N:21]=[CH:22][NH:23][C:24](=O)[C:25]=3[S:26][C:18]=2[CH:17]=[CH:16][CH:15]=1>ClCCCl>[Cl:10][C:24]1[C:25]2[S:26][C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([O:13][CH3:12])[C:19]=3[C:20]=2[N:21]=[CH:22][N:23]=1
Reactant: COc1cccc2sc3c(=O)[nH]cnc3c12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cccc2sc3c(Cl)ncnc3c12
Temperature: 25 °C
Yield: 66.1 %

Procedure:
DMF (0.125 mL, 1.7 mmol) is added dropwise to a solution of (COCl)2 (0.15 mL, 1.68 mmol) in 1,2-dichloroethane (4.5 mL) at r.t. After gas evolution ceases, 9-methoxy-4-oxo-3H-benzothieno[3,2-d]pyrimidine (73.2 mg, 0.32 mmol) is added. The resulting mixture is heated at reflux for 4hr. After the reaction is cooled to r.t., the black tar is filtered off. The filtrate is stripped to dryness and then mixed with water. A yellow solid forms and is collected via filtration. The solid is washed with water and air dried to give 4-chloro-9-methoxybenzothieno[3,2-d]pyrimidine (53 mg, 66%). 1H NMR (DMSO) δ9.17 (1H, s), 7.82-7.78 (2H, m), 7.3-7.2 (1H, m), 4.06 (3H, s).
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[C:15]([C:16](=[O:22])[C:17]2[S:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:7]2[CH2:8][CH:9]([C:11](Cl)=[O:12])[O:10][C:6]=2[C:5]=1[Cl:23].CO.[Cl-].[NH4+]>>[C:11]([CH:9]1[CH2:8][C:7]2[CH:14]=[C:15]([C:16](=[O:22])[C:17]3[S:21][CH:20]=[CH:19][CH:18]=3)[C:4]([Cl:3])=[C:5]([Cl:23])[C:6]=2[O:10]1)(=[O:12])[CH3:1]
Reactant: [Li]C
Reactant: O=C(c1cccs1)c1cc2c(c(Cl)c1Cl)OC(C(=O)Cl)C2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(=O)C1Cc2cc(C(=O)c3cccs3)c(Cl)c(Cl)c2O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Cuprous iodide (5.7 g., 0.03 mole) is placed in a 250 ml. three-necked round-bottom flask equipped with a magnetic stirring bar, septum stopper, nitrogen inlet and CaSO4 drying tube. The flask is flame dried while purging it with nitrogen. Diethyl ether (80 ml.) is added and the flask is cooled to 0° C. Methyl lithium (42.8 ml. of 1.4 M solution, 0.06 mole) is added to the stirred mixture. After ten minutes at 0° C. the temperature is lowered to -78° C. A cooled etheral solution (25 ml.) of 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carbonyl chloride (3.6 g., 0.01 mole) is added. After stirring 15 minutes at -b 78° C., the reaction is quenched by adding methanol (3.52 g., 0.011 mole). The reaction mixture is allowed to warm up to 25° C. and then is poured into 150 ml. of saturated aqueous ammonium chloride. The mixture is extracted with ether (3×50 ml.). The ether extracts are combined, dried over MgSO4 and evaporated in vacuo to give 2-acetyl-6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([CH3:11])[N:5]=[C:4]([SH:12])[N:3]=1.[OH-].[Na+].C(=O)([O-])O.[Na+].Cl[CH:21]([CH3:25])[C:22](=[O:24])[CH3:23].[Cl-].C([N+](CC)(CC)CCC1C=CC=CC=1)C>O.O1CCCC1.CC(=O)C>[OH:10][CH2:9][CH2:8][C:7]1[C:2](=[O:1])[NH:3][C:4]([S:12][CH:21]([CH3:25])[C:22](=[O:24])[CH3:23])=[N:5][C:6]=1[CH3:11]
Reactant: Cc1nc(S)nc(O)c1CCO
Reactant: CC(=O)C(C)Cl
Agent: CC[N+](CC)(CC)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)C(C)Sc1nc(C)c(CCO)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 30 parts of 4-hydroxy-2-mercapto-6-methyl-5-pyrimidineethanol, 6.8 parts of sodium hydroxide, 15 parts of sodium hydrogen carbonate and 100 parts of 2-propanone was stirred at room temperature and there were added 180 parts of tetrahydrofuran and 170 parts of water. Then there were added at once 25 parts of 3-chloro-2-butanone and 0.2 parts of N,N,N-triethylbenzeneethanaminium chloride and the whole was stirred and heated for 1 hour at 60° C. Stirring was continued overnight at room temperature. The reaction mixture was filtered and the filtrate was salted out. The organic phase was separated, dried, filtered and evaporated, yielding 36 parts of 5-(2-hydroxyethyl)-6-methyl-2-[(1-methyl-2-oxopropyl)thio]-4(3H)pyrimidinone as an oily residue (intermediate 7).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:4][N:3]=1.C1(C(C2C=CC=CC=2)=[NH:20])C=CC=CC=1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[CH:10]1([CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:20])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: Brc1ccc(OCC2CC2)cn1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Nc1ccc(OCC2CC2)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
A mixture of 2-bromo-5-(cyclopropylmethoxy)pyridine (5.65 g), tris(dibenzylideneacetone)dipalladium(0) (454 mg), 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine) (925 mg), 1,1-diphenylmethanimine (5.42 g), sodium t-butoxide (3.33 g) and toluene (50 mL) was stirred at 80° C. for 3 hr under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with THF (15 mL). 1M Hydrochloric acid (15 mL) was added thereto, and the mixture was stirred at room temperature for 30 min. 6M Hydrochloric acid (6 mL) was added thereto, and the organic layer was separated from the aqueous layer. The separated organic layer was extracted with 1M hydrochloric acid. The combined aqueous layer was neutralized with 8M aqueous sodium hydroxide solution, and extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (hexane/diethyl ether) to give the title compound as colorless crystals (3.67 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20]([OH:22])=O)=[O:17])=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:70]([NH2:77])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1>CN(C)C=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[OH:17][C:16]1([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:27])([CH3:1])[CH3:28])[CH:8]=[CH:9]3)[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20](=[O:22])[N:77]1[CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1
Reactant: C[Si](C)(C)CCOCn1ccc2cc(C(=O)c3ccccc3C(=O)O)ccc21
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc2cc(C3(O)c4ccccc4C(=O)N3Cc3ccccc3)ccc21
Temperature: 60 °C
Yield: 57.4 %

Procedure:
Crude 2-{[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indol-5-yl]carbonyl}benzoic acid (0.32 mmol) was taken up in N,N-dimethylformamide (1.0 mL), and treated with 4-methylmorpholine (0.14 mL, 1.3 mmol), HOAt (0.065 g, 0.48 mmol), HATU (0.16 g, 0.42 mmol) and benzylamine (0.070 mL, 0.64 mmol) and heated for 12 h at 60° C. The solution was diluted with saturated aqueous sodium bicarbonate solution and ethyl acetate and the layers were separated. The aqueous layer was extracted (2×100 mL ethyl acetate) and the combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo. Column chromatography (silica gel, 3:1 hexanes/ethyl acetate) gave 0.089 g (58%) of 3-hydroxy-2-(phenylmethyl)-3-[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indol-5-yl]-2,3-dihydro-1H-isoindol-1-one. 1H NMR (400 MHz, d6-CDCl3): 8.10 (d, 1H), 7.97 (m, 2H), 7.69 (m, 3H), 7.56 (m, 5H), 7.42 (m, 4H), 7.34 (m, 1H), 5.49 (m, 2H), 3.51 (m, 2H), 0.95 (m, 2H), 0.00 (s, 9H).