Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]([O:14]CC)=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].OC1C=C2C(CCC2=O)=CC=1OC>>[OH:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[C:12](=[O:14])[CH2:11][CH2:10]2
Reactant: CCOC(=O)C=Cc1ccc(OC)c(O)c1
Agent: COc1cc2c(cc1O)C(=O)CC2
Product: COc1cc2c(cc1O)CCC2=O

Procedure:
5-Hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-one 18b was prepared from 35b according to the protocol described for the preparation of compound 18a in Example 33 (Scheme 11). Isolated as light brown powder in 67% overall yield (3.55 g). 1H NMR (300 MHz, CDCl3): δ 2.69 (2H, m); 3.03 (2H, m); 3.92 (3H, s); 4.28 (1H, broad s); 6.92 (1H, s); 7.17 (1H, s). 13C NMR (75 Hz, CDCl3): δ 24.65; 35.86; 55.05; 103.68; 111.00; 127.98; 147.67; 151.32; 153.72; 206.88.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:11]=2)[CH2:3]1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:16][C:17]([F:26])([F:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:11]=2)[CH2:3]1
Reactant: Oc1ccccc1C(F)(F)F
Reactant: COC(=O)c1cnc(N2CCC(O)C2)s1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 2-(3-hydroxypyrrolidin-1-yl)-1,3-thiazole-5-carboxylate (1 g, 4.4 mmol), 2-(trifluoromethyl)phenol (0.8 g, 4.9 mmol) and triphenylphosphine (1.5 g, 5.7 mmol) in THF at rt was added DEAD (900 μL, 5.7 mmol) over 5-10 min. The mixture was stirred at rt for 2 days. Solvent was evaporated. The residue was diluted with EtOAc and washed successively with 1 N aqueous NaOH and brine. The EtOAc layer was separated, dried (Na2SO4) and concentrated. CombiFlash chromatography (40 g, 30-70% EtOAc in hexanes in 20 min, 35 mL/min, 18 mL/fraction) gave a semi-solid which was triturated with hexanes-diethyl ether to give a white solid which was filtered off. Crystals appeared in the mother liquor after standing. These crystals were collected to give the title compound, contaminated with about 5-10% impurity. 1H NMR (400 MHz, acetone-d6): δ 7.84 (s, 1 H), 7.67 (m, 2 H), 7.41 (d, 1 H), 7.17 (t, 1H), 5.51 (s, 1H), 3.95 (m, 1H), 3.80-3.65 (m, 6H), 2.60-2.46 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[O:9]1[CH2:13][CH2:12]OC1=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:12][CH2:13][OH:9])[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnn(CCO)c1
Temperature: 100 °C

Procedure:
A solid mixture of 4-nitro-1H-pyrazole (1 g, 8.84 mmol), 1,3-dioxolan-2-one (3.89 g, 44.2 mmol) and cesium carbonate (2.88 g, 8.84 mmol) was suspended in 20 ml dimethylformamide and the resulting suspension was slowly heated to 100° C. overnight. The mixture was added to 100 ml water and 40 ml ethyl acetate; the separated aqueous layer was extracted with ethyl acetate (30 ml), and the combined organic layers were washed with brine (30 ml), dried with magnesium sulfate, filtered and concentrated. The residue was flash chromatographed (50 mm; 2% methanol/methylene chloride then 4% methanol/methylene chloride) to give the title compound with some residual DMF.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:52])([CH3:51])[CH2:35][CH:36]([Sn:38]([CH2:47][CH2:48][CH2:49][CH3:50])([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][CH3:42])O)=[CH:30][CH:29]=1>C(Cl)Cl.C(#N)C>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:52])([CH3:51])[CH2:35][CH:36]([I:25])[Sn:38]([CH2:47][CH2:48][CH2:49][CH3:50])([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:30][CH:29]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C(O)CC(C)(C)c1ccc(Cl)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC#N
Product: CCCC[Sn](CCCC)(CCCC)C(I)CC(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.4 %

Procedure:
A solution of 14.0 grams (0.053 mole) of triphenylphosphine in about 54 mL of methylene chloride was stirred, and 3.6 grams (0.053 mole) of imidazole was added. Upon completion of addition, the reaction mixture was stirred about 45 minutes until the imidazole dissolved. The reaction mixture was then cooled in an ice bath, and 13.6 grams (0.053 mole) iodine was added portionwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature, where it stirred for about 15 minutes until the iodine dissolved. After this time the reaction mixture was cooled to 0° C., and a solution of 17.4 grams (0.036 mole) of 3-(4-chlorophenyl)-3-methyl-1-tributylstannylbutanol in about 36 mL of methylene chloride was added dropwise while maintaining the reaction mixture temperature below 5° C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about 18 hours. The reaction mixture was then taken up in about 100 mL of acetonitrile and extracted with three 150 mL portions of hexane. The combined extracts were concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using petroleum ether as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.7 grams of 3-(4-chlorophenyl)-3-methyl-1-iodo-1-tributylstannylbutane. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][C:7]#[N:8].[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH:20]=O)=[CH:15][N:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[C:7]([NH2:8])=[N:19][C:17]3[N:18]=[C:13]([NH2:12])[N:14]=[CH:15][C:16]=3[CH:20]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(CC#N)c1
Reactant: Nc1ncc(C=O)c(N)n1
Product: COc1cccc(-c2cc3cnc(N)nc3nc2N)c1

Procedure:
The title compound was prepared according to Example 1, starting from 3-methoxybenzyl cyanide and 2,4-diamino-5-pyrimidine-carboxaldehyde; mp 284°-286 ° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][CH3:13])=[N:7][CH:6]=[CH:5]2.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-])=O.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.[Cl-].[Na+].O>[CH3:27][S:28]([NH:14][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([O:12][CH3:13])=[N:7][CH:6]=[CH:5]3)(=[O:25])=[O:24])=[CH:19][CH:18]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: COc1nccc2cc(N)ccc12
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: COc1nccc2cc(NS(=O)(=O)c3ccc(NS(C)(=O)=O)cc3)ccc12
Reaction time: 4 h

Procedure:
The compound synthesized using 6-amino-1-methoxyisoquinoline (Production Example 43b) and 4-nitrobenzenesulfonyl chloride in the same manner as in Synthetic Example 1b was processed in the same manner as in Production Example 170b, to reduce the nitro group thereof. The resulting compound was dissolved in pyridine and methanesulfonyl chloride was added thereto under ice-cooling, followed by stirring for 4 hours as it was. Brine was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column and the resulting crystals were recrystallized from ethanol, to give the title compound.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[Cl-].[NH4+]>O1CCCC1>[OH:18][CH:17]([C:16]1[CH:19]=[CH:20][C:13]([OH:12])=[CH:14][CH:15]=1)[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: O=Cc1ccc(O)cc1
Reactant: C#CC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc(O)cc1
Reaction time: 0.17 h

Procedure:
A solution of 12.5 ml (0.15 mol) of methyl propiolate in 150 ml of tetrahydrofuran was treated at -78° under argon with 100 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 9.8 g (80 mmol) of 4-hydroxybenzaldehyde in 50 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 20 minutes, then brought to room temperature and treated with 200 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were dried in sequence with saturated sodium sulphate and concentrated The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-hydroxy-4-(4-hydroxyphenyl)-2-butynoate as a red oil.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[NH:37]N>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[N:37]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)(=[O:22])=[O:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCC3)c2)ccc1=O
Reactant: NNc1cc(F)ccc1F
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCC3)c2)nc1-c1ccnn1-c1cc(F)ccc1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-29) and 2,5-difluoro-phenylhydrazine according to the method described for example 91. MS: M=484.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:20])[CH2:17][O:18][CH3:19])[CH2:8][C@H:7]([NH2:21])[C:6]1=[O:22].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[CH2:34]Br.C([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:20])[CH2:17][O:18][CH3:19])[CH2:8][C@H:7]([N:21]=[CH:34][C:25]2[CH:26]=[CH:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:24]=2)[C:6]1=[O:22]
Reactant: COCC(=O)N1C[C@H](N)C(=O)N(CC(=O)OC)c2ccccc21
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COCC(=O)N1C[C@H](N=Cc2ccc3ccccc3c2)C(=O)N(CC(=O)OC)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
To a solution of 638 (630 mg, 1.76 mmol) and 2-naphthylmethyl bromide (428 mg, 1.94 mmol) in CH3CN was added K2CO3 (608 mg, 4.4 mmol). The resulting mixture was stirred at ambient temperature. After 18 hours, the reaction mixture was diluted with CH2Cl2, washed with water then brine, dried over Na2SO4 then concentrated in vacuo. Flash chromatography (SiO2, 0 to 20% EtOAc/CH2Cl2) afforded 450 mg of 639.
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([O:12][CH:13]([F:15])[F:14])[CH:5]=1)[CH:2]=C.N1C=CC=CC=1.[O:22]=[O+][O-]>C(Cl)Cl.CO>[F:14][CH:13]([F:15])[O:12][C:6]1[CH:5]=[C:4]([CH2:1][CH:2]=[O:22])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: C=CCc1ccc(C#N)c(OC(F)F)c1
Reactant: O=[O+][O-]
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(CC=O)cc1OC(F)F
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A solution of 4-allyl-2-(difluoromethoxy)benzonitrile (600 mg, 2.9 mmol) in 1:1 CH2Cl2/MeOH (15 mL) containing pyridine (0.5 mL, 6 mmol) was cooled to −78° C., and O3 was passed through until a blue color was present. N2 was then bubbled through to discharge the blue color and Me2S (5 ml) was added. The reaction mixture was allowed to warm and left overnight. The mixture was washed with 1 N HCl, aqueous NaHCO3, dried and concentrated to give crude 2-(difluoromethoxy)-4-(2-oxoethyl)benzonitrile.
Reaction SMILES: C([O:4][C:5]1[C:13]([O:14]C)=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[C:16]#[N:17])(=O)C.P(Br)(Br)Br>ClCCl>[OH:14][C:13]1[CH:12]=[C:8]([CH:7]=[C:6]([C:16]#[N:17])[C:5]=1[OH:4])[C:9]([OH:11])=[O:10]
Reactant: COc1cc(C(=O)O)cc(C#N)c1OC(C)=O
Agent: BrP(Br)Br
Solvent: ClCCl
Product: N#Cc1cc(C(=O)O)cc(O)c1O
Temperature: 25 °C

Procedure:
To a solution containing 2.3 g of 4-acetoxy-3-cyano-5-methoxybenzoic acid in 10 ml of dichloromethane 40 ml of 1 molar PBr3 in dichloromethane was added. The mixture was stirred over night at room temperature. The solvent was evaporated in vacuo and to the residue ice-water was added. The product was filtered and washed with water. Yield 1.25 g (74%), m.p. 269°-271° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([O:20]CCC)=O.[NH2:24][C:25]1[S:26][C:27]2[CH2:33][CH2:32][CH2:31][CH2:30][C:28]=2[N:29]=1>>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:15])(=[O:16])[N:4]([CH3:17])[C:3]=1[C:18]([NH:24][C:25]1[S:26][C:27]2[CH2:33][CH2:32][CH2:31][CH2:30][C:28]=2[N:29]=1)=[O:20]
Reactant: Nc1nc2c(s1)CCCC2
Reactant: CCCOC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2nc3c(s2)CCCC3)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 58 %

Procedure:
Prepared analogous to Example 1 from propyl 4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-4,5,6,7-tetrahydrobenzothiazole with a yield of 58% of theory.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15](=[O:17])[NH:14][C:13]=2[CH:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:22]>CN(C)C=O.O.C(OCC)(=O)C>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15](=[O:17])[N:14]([CH3:22])[C:13]=2[CH:18]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2oc(=O)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2ccc(O[Si](C)(C)C(C)(C)C)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
To a cooled (0° C.) solution of 5-{[tert-butyl(dimethyl)silyl]oxy}-1,3-benzoxazol-2(3H)-one (1.45 g, 5.4 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added sodium hydride (0.26 g, 60% dispersion in mineral oil, 6.6 mmol). The reaction mixture was stirred at 0° C. for 15 min followed by the addition of iodomethane (1.0 mL, 16 mmol). The reaction mixture was stirred at ambient temperature for 16 h and diluted with water (20 mL) and ethyl acetate (20 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic solution was washed with water (5×20 mL) and brine (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography with ethyl acetate in hexanes (0 to 25% gradient) to afford 5-{[tert-butyl(dimethyl)silyl]oxy}-3-methyl-1,3-benzoxazol-2(3H)-one (1.26 g, 83%) as a pale yellow solid: 1H NMR (300 MHz, CDCl3) δ7.02 (d, J=8.6 Hz, 1H), 6.55 (dd, J=8.6, 2.4 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 3.35 (s, 3H), 0.99 (s, 9H), 0.20 (s, 6H).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](Br)=[CH:21][CH:20]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[Br:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([C:12]2[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=4[CH:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:20]=1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Reactant: Brc1ccc(Br)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: Brc1cc(-c2cc3ccccc3c3ccccc23)cc2ccccc12
Temperature: 85 °C
Reaction time: 6 h
Yield: 47.8 %

Procedure:
In argon atmosphere, a mixture of 19.41 g (87.4 mmol) of 9-phenanthreneboronic acid, 25.00 g (87.4 mmol) of 1,4-dibromonaphthalene, 2.02 g (1.70 mmol) of tetrakis(triphenylphosphine)palladium (0), 50 ml of dimethoxyethane, 200 ml of toluene, and 132 g of a 2 M sodium carbonate aqueous solution was stirred at a bath temperature of 85° C. for 6 h. The reaction mixture was added with water and extracted with toluene. After washing with water, the organic phase was dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel chromatography to obtain 16.02 g (yield: 55.0%) of 4-bromo-2-(9-phenanthrenyl)naphthalene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH2:19][C:20](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[O:44]1[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=2[O:47][CH2:46][CH:45]1[CH2:54][NH2:55]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH2:19][CH2:20][NH:55][CH2:54][CH:45]1[O:44][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=2[O:47][CH2:46]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1COc2ccccc2O1
Reactant: O=C(O)CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc3[nH]cc(CCCNCC4COc5ccccc5O4)c3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
5-Benzyloxyindole-3-propionic acid (2.7 g, 9.1 mmole), 1-hydroxybenzotriazole hydrate (1.5 g, 10.9 mmole) and 1,3-diisopropylcarbodiimide (3.4 ml, 21.8 mmole) were combined in 200 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.8 g, 9.1 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and replaced with dichloromethane. The mixture was then washed with H2O. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on silica gel using first dichloromethane and then 2.5% methanol in dichloromethane as eluants to give 3.2 g (79%) of the desired product, (2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-(5-benzyloxy-1H-indol-3-yl)-propanamide, as a light tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:36])C=1.[OH-:39].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:20])(=[O:36])=[O:39])=[CH:17][CH:18]=3)=[N:10][C:9]=2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [OH-]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2nc(-c3cccc(C)c3)c(-c3ccnc(F)c3)s2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)sc2-c2ccnc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazole (2.7 g, 6.9 mmol) in N,N-dimethylformamide (60 mL) was added m-chloroperbenzoic acid (3.3 g, 14 mmol) and the mixture was stirred at room temperature for 1 hour. An 8N aqueous solution of sodium hydroxide was added to the reaction mixture and the resulting solid was collected by filtration. This solid was recrystallized from ethanol to obtain 2.5 g (yield 85%) of the title compound.
Reaction SMILES: Cl.FC1C([O:9][C:10]([C:12]2[N:13]=[N:14][C:15]([CH2:31][CH2:32][CH2:33][CH3:34])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)[CH:17]=2)=O)=C(F)C(F)=C(F)C=1F.N1C=CC=CC=1.[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][O:55][CH:54]([CH2:58][NH2:59])[CH2:53]1)=[O:51])([CH3:48])([CH3:47])[CH3:46]>C1COCC1>[C:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][O:55][CH:54]([CH2:58][NH:59][C:10]([C:12]2[N:13]=[N:14][C:15]([CH2:31][CH2:32][CH2:33][CH3:34])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:20][CH:19]=3)[CH:17]=2)=[O:9])[CH2:53]1)=[O:51])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C1
Reactant: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCc1nnc(C(=O)NCC2CN(C(=O)OC(C)(C)C)CCO2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C

Procedure:
To a solution of 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester hydrochloride (0.18 mmol, 0.1 g, Example 90) and 0.1 mL of pyridine in 2 mL of THF was added 2-aminomethyl-morpholine-4-carboxylic acid tert-butyl ester (0.4 mmol, 0.09 g). The mixture was shaken at room temperature, and upon completion of the reaction, the solvent was removed. The residue was chromatographed with 4% methanolic solution of ammonia (2.0 M ammonia in methanol) in EtOAc to provide 2-({[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-methyl)-morpholine-4-carboxylic acid tert-butyl ester. LCMS: m/z 553.0 [M+1].
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[CH:3][C:2]=1[C:11](OCC)=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[CH:3][C:2]=1[CH2:11][OH:12]
Reactant: CCOC(=O)c1cnc2c(n1)CCCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OCc1cnc2c(n1)CCCC2
Reaction time: 0.75 h
Yield: 78.5 %

Procedure:
To a solution of 0.16 g of ethyl 5,6,7,8-tetrahydroquinoxaline-2-carboxylate in 1.5 mL of tetrahydrofuran, 29 mg of lithium aluminum hydride was added under cooling with ice, the mixture was stirred for 45 minutes, 29 mg of lithium aluminum hydride was further added thereto, and the mixture was stirred for 30 minutes. Thereto were added ethyl acetate and water, the insoluble substance was filtered off, sodium chloride was added to a filtrate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.10 g of (5,6,7,8-tetrahydroquinoxalin-2-yl)methanol as a brown solid.