Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=2[F:26])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:32].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=2[F:26])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:17][O:32]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCCC(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCCCC1CO1)c1c(F)ccc(F)c1F

Procedure:
[7-(4-chloro-benzenesulfonyl)-7-(2,3,6-trifluoro-phenyl)-1-heptene (0.65 g, 1.6 mmole) and mCPBA (77%, 0.71 g, 3.2 mmole) were stirred in 50 mL DCM for 5 hours. 2 g Na2S2O3 in 100 mL water were added to quench excess mCPBA. The organic layer was separated, washed with 1N NaOH solution (50 mL), brine (50 mL), dried over Na2SO4 and concentrated. The product was purified by column chromatography using EtOAc/Hexane as eluent (Gradient from 0/100 to 40/60 in 40 minute, 0.52 g, 77%). 1H NMR (CDCl3, 400 MHz) δ 7.63 (d, j=8.05 Hz, 2H), 7.45 (d, j=8.05 Hz, 2H), 7.15 (m, 1H), 6.83 (m, 0.5), 6.74 (m, 0.5H), 4.58 (dd, j=5.1 and 6.5 Hz, 1H), 2.84 (m, 1H), 2.71 (t, j=4.4 Hz, 1H), 2.41 (dd, j=2.9 and 5.1 Hz), 2.45 (m, 1H), 2.34 (m, 1H), 1.25-1.55 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19](Br)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:29][C:30]1[C:35]([CH3:36])=[CH:34][C:33]([Br:37])=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:29]=[C:30]4[C:35]([CH3:36])=[CH:34][C:33]([Br:37])=[CH:32][N:31]4[C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Br)cnc1N
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1cc(Br)cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Temperature: 130 °C
Yield: 17.2 %

Procedure:
1.25 g (2.81 mmol) {1-[4-(2-Bromo-2-phenyl-acetyl)phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, 631.4 mg (3.38 mmol) 2-amino-5-bromo-3-methyl-pyridine, 2.15 g molecular sieves (4 Å, dried over night at 120° C. in a drying oven), 363.5 mg (2.81 mmol) N,N-diisopropylethylamine in 12 mL 2-propanol (degassed for 15′) in a microwave vial, sealed with a microwave cap, were heated at 130° C. for 17 hours in a heating block. The reaction mixture was sucked off via a glass fibre filter and the filter was washed with dichloromethane. After evaporation to dryness, the residue was redissolved in dichloromethane (200 mL), washed with an 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate (50 mL) and brine (100 mL) and dried (sodium sulfate). After filtration and removal of the solvent the residue was purified by chromatography on silicagel (eluents: hexane/ethyl acetate) yielding 256.7 mg (17.1%) of the title compound.
Reaction SMILES: [CH:1]1([C@@H:4]([NH:9][C:10]2[C:22]3[C:21]4[CH:20]=[CH:19][C:18](I)=[CH:17][C:16]=4[NH:15][C:14]=3[C:13]([C:24]([NH2:26])=[O:25])=[CH:12][N:11]=2)[C:5]([F:8])([F:7])[F:6])[CH2:3][CH2:2]1.[Si:27]([C:31]#[CH:32])([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C.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.[Cu]I>[CH:1]1([C@@H:4]([NH:9][C:10]2[C:22]3[C:21]4[CH:20]=[CH:19][C:18]([C:32]#[C:31][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:17][C:16]=4[NH:15][C:14]=3[C:13]([C:24]([NH2:26])=[O:25])=[CH:12][N:11]=2)[C:5]([F:8])([F:7])[F:6])[CH2:3][CH2:2]1
Reactant: C#C[Si](C)(C)C
Reactant: NC(=O)c1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(I)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc2c(c1)[nH]c1c(C(N)=O)cnc(N[C@H](C3CC3)C(F)(F)F)c12
Temperature: 50 °C

Procedure:
A mixture of 1-{[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]amino}-7-iodo-5H-pyrido[4,3-b]indole-4-carboxamide (0.19 g, 0.40 mmol), TMS acetylene (0.12 g, 1.2 mmol), Pd(PPh3)4 (0.047 g, 0.040 mmol), CuI (0.015 g, 0.081 mmol), and TEA (0.082 g, 0.81 mmol) in DMF (4 mL) was purged with nitrogen for 5 min, heated to 50° C. overnight, and cooled to room temperature. The mixture was diluted with EtOAc, washed with water and brine, dried (sodium sulfate), concentrated, and purified by flash chromatography to afford the title compound.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16]CC)=[O:15])[O:3]1.[Li+].[OH-].Cl>CO.O>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([OH:16])=[O:15])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(O)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (500 mg, 2.0 mmol) in 2 mL MeOH was added LiOH (240 mg, 10 mmol) in 5 ml H2O dropwise at 0° C. The reaction mixture was stirred at room temperature for 1.5 h and acidified by 1 N HCl to pH=5.0. The mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated to dryness. The residue was used directly in next step reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1N.C(ON=O)(C)(C)C.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[Cu]>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:4]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:3]=2[O:2][CH3:1])=[CH:23][CH:22]=1
Reactant: Clc1ccccc1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: COc1cc([N+](=O)[O-])ccc1-c1ccc(Cl)cc1

Procedure:
2-Methoxy4-nitroaniline 5 and chlorobenzene are heated in the presence of t-butylnitrite and copper powder to give 2-(4-chlorophenyl)-5-nitroanisole 6. Hydrogenation of 6 with platinum oxide in methanol (a base such as morpholine may be used) provides the desired biphenyl amine 3.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nc(-c2cccc(N)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Reaction time: 0.5 h

Procedure:
The reaction of tert-butyl 5-amino-2-methylthio-4(3-aminophenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 9e, 100 mg) with ethyl chloroformate (247 μl) was performed using the methods described in example 15. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/10% aq. CH3CN=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH2:15][C:16]1[S:17][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[C:19]([OH:21])[N:20]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:28][C:24]1[CH:23]=[C:22]([CH:18]2[S:17][C:16]([NH:15][C:12]([C:3]3[C:2]([OH:1])=[C:11]4[C:6]([CH:7]=[CH:8][CH:9]=[N:10]4)=[CH:5][CH:4]=3)=[O:14])=[N:20][C:19]2=[O:21])[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1nc(O)c(-c2cccc(Cl)c2)s1
Reactant: O=C(O)c1ccc2cccnc2c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1=NC(=O)C(c2cccc(Cl)c2)S1)c1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 168 h
Yield: 30.5 %

Procedure:
To a solution of 8-hydroxyquinoline-7-carboxylic acid (0.284 g) of Preparation 1 and 2-amino-5-(3-chlorophenyl)-4-hydroxy-1,3-thiazole (0.340 g) in 20 mL DMF is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxybenzotriazole monohydrate (0.217 g). The mixture is stirred at room temperature for 7 days. The solution is then poured into 30 mL ice-water. The resulting solid is collected and dried. The crude product is triturated with hot EtOAc, then with hot i-PrOH to yield 0.182 g of the title product as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[CH3:32][O:33][C:34](=[O:44])[CH2:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38](Br)[CH:37]=1>>[CH3:32][O:33][C:34](=[O:44])[CH2:35][C:36]1[CH:37]=[C:38]([C:14]2[CH:15]=[CH:16][C:17]([C:19]([F:21])([F:22])[F:20])=[CH:18][C:13]=2[CH2:12][N:3]([C:4](=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:1][CH3:2])[CH:39]=[C:40]([Cl:42])[CH:41]=1
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)c1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: N-ethyl-N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-benzamide and (3-bromo-5-chloro-phenyl)-acetic acid methyl ester.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([OH:38])[CH2:10][CH:11]([NH:25][C:26](=[O:37])[C@@H:27]([NH:32][C:33]([O:35][CH3:36])=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>O>[CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([OH:38])[CH2:10][C@H:11]([NH:25][C:26](=[O:37])[C@@H:27]([NH:32][C:33]([O:35][CH3:36])=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@H](C(=O)NC(Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: CO
Solvent: O
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 45 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
A 12 L 3-necked round bottom flask was charged with 169.74 gm of the product of Example 111-12 and 3.5 L of methanol, warmed to 45° C., water (1.75 L) was slowly added, stirred at 45-48° C. for about 1 hour, and cooled to ambient temperature overnight. The slurry was filtered and washed with 2:1 methanol:water, suction dried for 1 hour and dried at 50° C. vacuum oven overnight to give 60.4 gm of the title compound (28:1 diastereomeric ratio as determined by HPLC (Column: XDB C8 15 cm, Eluent: CH3CN/10 mM Na2HPO4 with H3PO4 adjusted to pH 7, Gradient: 10% CH3CN to 90% CH3CN in 15 min, then hold for 10 min, column oven temperature: 35° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[N:4]1[CH:3]=[C:2]([CH:10]=[CH:9][C:8]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[N:6][CH:5]=1
Reactant: Brc1cncnc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1cncnc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 71.9 %

Procedure:
A mixture of 5-bromopyrimidine (5.93 g), ethyl acrylate (5.08 g), palladium acetate (0.112 g), triphenyl phosphine (0.23 g) and triethylamine (4.5 g) was stirred at 150° C. in a pressure vessel for 6 hours. After cooling overnight, water (50 ml) was added to the dark residue, and the product was extracted into toluene. Drying, charcoaling and evaporation gave a pale oil, which was triturated with pet, ether to obtain ethyl 3-(5-pyrimidyl)acrylate (4.78 g). 1H-NMR (CDCl3) δ 1.36 (3H, t), 4.27 (2H, q), 6.59 (1H, d), 7.62 (1H, d), 8.88 (2H, s), 9.20 (1H, s).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:20][CH2:19]1.CCCCCC>O>[OH:16][C:8]1[CH:7]=[CH:6][C:5]([C@@H:3]([OH:4])[CH2:2][NH:1][CH:36]2[CH2:35][CH2:34][N:33]([C:30]3[CH:29]=[CH:28][C:27]([S:24]([N:21]4[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]4)(=[O:26])=[O:25])=[CH:32][CH:31]=3)[CH2:38][CH2:37]2)=[CH:10][C:9]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CN1CCN(S(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)CC1
Solvent: CCCCCC
Solvent: O
Product: CN1CCN(S(=O)(=O)c2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)CC1

Procedure:
The title compound was prepared from N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide, and 1-{4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-4-piperidinone in substantially the same manner, as described in Example 50. The product was obtained as a brown solid; mp: 89-91° C.; 1H NMR (400 MHz, DMSO-d6): δ 1.53-1.65 (m, 2H), 2.06-2.16 (m, 2H), 2.82-2.89 (m, 2H), 2.94 (s, 3H), 3.09-3.13 (m, 2H), 3.70 (brs, 2H), 4.01-4.05 (m, 2H), 4.76-4.79 (d, 2H), 6.11 (brs, 1H), 6.88-6.90 (d, 2H), 7.06-7.13 (m, 4H), 7.25 (s, 1H), 7.52-7.55 (d, 2H), 8.60 (brs, 1H); 8.58 (brs, 1H); 8.75 (s, 1H), 9.64 (brs, 1H), 10.00 (s, 1H); MS m/z 568 (M+H)+; Analysis for C25H37N5O6S2×0.4 hexane×0.52 H2O Calc'd: C, 42.07; H, 4.93; N, 7.34; Found: C, 42.27; H, 4.60; N, 6.70.
Reaction SMILES: ClCCl.Cl[C:5]1[C:6]2[CH:13]=[CH:12][NH:11][C:7]=2[N:8]=[CH:9][N:10]=1.[CH3:14][Mg]Br>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][C:5]1[C:6]2[CH:13]=[CH:12][NH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: C[Mg]Br
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ncnc2[nH]ccc12
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 15.9 %

Procedure:
Into a round bottom flask the catalyst [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 1:1 complex with dichloromethane (70.0 mg, 0.09 mmol), is placed under nitrogen with 15 mL of toluene along with a stir bar. A suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 1.47 g, 9.57 mmol) in 15 mL of toluene is added at room temperature. After stirring for 10 minutes, methylmagnesium bromide (17.00 mL, 3.00 M in ether, 51.00 mmol) is added dropwise. The solution is slowly heated to 60° C. and stirred for 3 hrs at 60° C., then overnight at room temperature. The resulting dark orange reaction mixture is quenched with 1 N hydrochloric acid and adjusted to pH ˜5, then extracted with ethyl acetate and water saturated with sodium chloride. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound as a yellow solid (8, 202 mg). 1H-NMR (dmso-d6) is consistent with the desired compound. MS (ESI) [M+H+]+=134.3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:14]([O-])=O)[N:5]=1)[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:14][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]=[CH:13][C:4]([O:3][CH2:1][CH3:2])=[N:5]2
Reactant: CCOc1ccc2c([N+](=O)[O-])cccc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(N)cccc2n1

Procedure:
860 mg (3.9 mmol) of 2-ethoxy-5-nitroquinoline is stirred in 25 ml of ethyl acetate in the presence of 235 mg of 10% Pd—C for 4.5 hours in a hydrogen atmosphere. The batch is filtered, and the filtrate is concentrated by evaporation: 720 mg of a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:36](O)[CH2:37][CH2:38][OH:39].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:36][CH2:37][CH2:38][OH:39]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc3ccccc23)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of 5-methyl-3-(1-naphthalenylsulfonyloxy)phenol (620 g, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (50 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as a yellow oil (650 mg, 87%). 1H-NMR (300 MHz, CDCl3) δ 8.80 (d, J=8.6 Hz, 1H), 8.14 (d, J=7.3 Hz, 2H), 7.98 (d, J=8.2 Hz, 1H), 7.78 (t, J=8.5 Hz, 1H), 7.67 (t, J=8.1 Hz, 1H), 7.49 (t, J=8.1 Hz, 1H), 6.54 (s, 1H), 6.33 (s, 1H), 6.22 (s, 1H), 3.84 (t, J=6.0 Hz, 2H), 3.75 (t, J=6.0 Hz, 2H), 2.15 (s, 3H), 1.90 (m, 2H), 1.59 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=1[C:22](=[O:26])[N:23]([CH3:25])[CH3:24])=[O:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[C:44]2[C:39](=[N:40][CH:41]=[C:42](B3OC(C)(C)C(C)(C)O3)[CH:43]=2)[N:38]([S:54]([C:57]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=2)(=[O:56])=[O:55])[CH:37]=1>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].O1CCCC1>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:42]2[CH:43]=[C:44]3[C:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[O:29][CH3:28])=[CH:37][N:38]([S:54]([C:57]4[CH:58]=[CH:59][C:60]([CH3:63])=[CH:61][CH:62]=4)(=[O:56])=[O:55])[C:39]3=[N:40][CH:41]=2)=[CH:17][C:16]=1[C:22](=[O:26])[N:23]([CH3:25])[CH3:24])=[O:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)c1cc(Br)ccc1NC(=O)NCCN(C)C(=O)OC(C)(C)C
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(NC(=O)NCCN(C)C(=O)OC(C)(C)C)c(C(=O)N(C)C)c3)cc12
Yield: 67.5 %

Procedure:
A mixture of {2-[3-(4-bromo-2-dimethylcarbamoyl-phenyl)-ureido]-ethyl}-methyl-carbamic acid tert-butyl ester (75 mg, 0.17 mmol), 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (85 mg, 0.168 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) dichloromethane adduct (13.7 mg) was dissolved in a mixture of acetonitrile (4 mL), 1 M aqueous sodium carbonate (4 mL) and tetrahydrofuran (1 mL). The mixture was irradiated in the microwave to 120° C. for 10 minutes. The reaction mixture was then concentrated and the residue was partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (0 to 100% [10% methanol in ethyl acetate] in hexanes) to give 84 mg (66%) of [2-(3-{2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-ureido)-ethyl]-methyl-carbamic acid tert-butyl ester. MS: m/z 741.5 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([OH:15])[CH:6]=1)=O.[NH2:16][C:17]1[S:18][CH:19]=[N:20][N:21]=1>C(O)CCC>[S:18]1[CH:19]=[N:20][N:21]2[CH:2]=[C:3]([C:5]3[CH:6]=[C:7]([OH:15])[C:8]([OH:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=3)[N:16]=[C:17]12
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: Nc1nncs1
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(-c2cn3ncsc3n2)cc(O)c1O
Temperature: 25 °C

Procedure:
A solution of 1.38 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and 505.7 mg of 2-amino-1,3,4-thiadiazole in 25 ml of n-butanol is heated to boiling under reflux for 7 hours. The reaction mixture is then cooled to room temperature and the separated crystals are filtered under suction. There is obtained 5-(imidazo-[2,1-b]-1,3,4-thiadiazol-6-yl)-3-nitropyrocatechol of m.p. 278°-280° (from methanol).
Reaction SMILES: Br.[Br-].[CH3:3][N:4]([CH3:27])[CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC.C([Li])CCC.O=[C:40]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[CH2:44][O:43][C:42]2[CH:51]=[CH:52][C:53]([C:55]([O:57][CH3:58])=[O:56])=[CH:54][C:41]1=2>O1CCCC1>[CH3:3][N:4]([CH3:27])[CH2:5][CH2:6][CH:7]=[C:40]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[CH2:44][O:43][C:42]2[CH:51]=[CH:52][C:53]([C:55]([O:57][CH3:58])=[O:56])=[CH:54][C:41]1=2
Reactant: COC(=O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1ccc2c(c1)C(=CCCN(C)C)c1ccccc1CO2

Procedure:
In this Example, 45 g of (3-dimethylaminopropyl)triphenylphosphonium bromide hydrobromide is suspended in 200 ml of tetrahydrofuran under a nitrogen atmosphere and 82 ml of 1.6N-n-butyl lithium hexane solution is added thereto under ice-cooling. The mixture is stirred under ice-cooling for one hour. To the mixture is dropwise added under ice-cooling a solution obtained by dissolving 10 g of methyl 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate in 200 ml of tetrahydrofuran. After stirring the mixture at room temperature for 2 hours, the mixture is extracted with 800 ml of ethyl acetate. After washing the extract with saturated aqueous sodium chloride solution and drying the extract over anhydrous sodium sulfate, the solvent is distilled away under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: hexane:ethyl acetate:triethylamine=10:10:1) to obtain 2.0 g of trans form and 5.6 g of cis form of the desired product.