Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH:12]1[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:25]O>>[N:11]1([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:16][CH2:15][O:14][CH2:13][CH:12]1[C:17]([O:19][CH3:25])=[O:18]
Reactant: O=C(O)C1COCCN1C(=O)OCc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1COCCN1C(=O)OCc1ccccc1
Temperature: 50 °C

Procedure:
4-(Benzyloxycarbonyl)morpholine-3-carboxylic acid (crude material, 21.2 g, about 75 mmol) was dissolved in methanol (250 ml). Sulfuric acid (12.01 ml, 225 mmol) was added slowly with vigorous stirring. An exotherm was noticed and the temperature rose to 34° C. after the addition. Once the addition was complete, reaction solution was heated to 50° C. for 18 hours. The reaction mixture was cooled to room temperature and concentrated to remove most of the methanol. EtOAc (500 ml) was added and the organic solution was washed with water (150 ml), saturated sodium bicarbonate solution (100 ml) and water (150 ml). The organic solution was then concentrated to give a residue which was purified by silica gel column (330 g silica gel, hexanes/EtOAc 5:1) to afford 15.9 gram of 4-benzyl 3-methyl morpholine-3,4-dicarboxylate as clear oil. 1H NMR (400 MHz, CDCl3) δ=3.28-3.57 (m, 2H), 3.67 (m, 1H), 3.57-3.96 (m, 5H), 4.4 (dd, 1H), 4.61 (dd, 1H), 5.19 (m, 2H), 7.32-7.4 (m, 5H)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH:23]=[CH:22][C:17]([NH:18]C(=O)C)=[C:16]([N+:24]([O-])=O)[CH:15]=2)[CH:7]=[CH:8][C:9]=1[NH:10]C(=O)C)([O-])=O.[N+]([O-])(O)=O>C1(C2C=CC(N)=CC=2)C=CC(N)=CC=1.C(OC(=O)C)(=O)C.C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([C:14]2[CH:23]=[CH:22][C:17]([NH2:18])=[C:16]([NH2:24])[CH:15]=2)[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: CC(=O)Nc1ccc(-c2ccc(NC(C)=O)c([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Agent: Nc1ccc(-c2ccc(N)cc2)cc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O=[N+]([O-])O
Product: Nc1ccc(-c2ccc(N)c(N)c2)cc1N

Procedure:
That is, amino groups in benzidine are first protected by N-acetylation with acetic anhydride, and the resulting acetylated compound is then converted into 3,3′-dinitro-N,N′-diacetylbenzidine by nitration. For example, this nitration is performed with concentrated nitric acid in a mixture of acetic anhydride and acetic acid. 3,3′-Dinitro-N,N′-diacetylbenzidine is treated with a base to remove the acetyl groups and then treated with tin (II) chloride in hydrochloric acid to reduce the nitro groups to yield 3,3′,4,4′-tetraaminobiphenyl (Scheme 1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=O)=[O:22])[C:16]=1[CH3:31].Cl.C(N=C=NCCCN(C)C)C.O[C:45]1[C:53]2[N:52]=N[NH:50][C:49]=2[CH:48]=[CH:47][CH:46]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:50][C:49]2[CH:48]=[CH:47][CH:46]=[CH:45][C:53]=2[NH2:52])=[O:30])=[O:22])[C:16]=1[CH3:31]
Reactant: Oc1cccc2[nH]nnc12
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCC(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
5-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-pentanoic acid (427 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (388 mg, 75% yield) as a red solid. LC-MS (m/z) 518 (M+1).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[C:19]([O:21][C:22]4[CH:27]=[C:26](Cl)[N:25]=[C:24]([NH2:29])[N:23]=4)[CH:18]=[CH:17][C:16]=23)=[O:11])[CH:6]=[CH:7][CH:8]=1>C1COCC1.[Pd]>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[C:19]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH2:29])[N:23]=4)[CH:18]=[CH:17][C:16]=23)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1nc(Cl)cc(Oc2ccc3c(C(=O)Nc4cccc(C(F)(F)F)c4)cnn3c2)n1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1nccc(Oc2ccc3c(C(=O)Nc4cccc(C(F)(F)F)c4)cnn3c2)n1

Procedure:
27 mg (0.064 mMol) 6-(2-Amino-6-chloro-pyrimidin-4-yloxy)-pyrazolo[1,5-a]pyridine-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide are dissolved in 2 ml THF and submitted to hydrogenation over Pd—C (Engelhardt 4045) for 2 h at rt. The reaction mixture is worked up by filtration and concentrated to give the title compound as a white solid: m.p.: 102-104° C.; MS: [M+1]+=415.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH2:3]>[Pd].C(O)C>[CH3:1][CH:2]([CH3:3])[CH2:4][CH2:5][C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: C=C(C)CCc1cc2ccccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CC(C)CCc1cc2ccccc2[nH]1
Reaction time: 2 h
Yield: 59 %

Procedure:
Into a 3-necked round bottom flask under a blanket of nitrogen was placed 5% palladium catalyst on charcoal (771 mg). A solution of 2-(2-methyl-1-buten-4-yl) indole (671 mg) in ethanol (36 ml) was added to the flask, which was evacuated and charged with hydrogen twice. The mixture was stirred vigorously under hydrogen (1 atmosphere) for 2 hours, followed by filtration through a pad of Celite. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography (3% ethyl acetate/hexane) to give 2-(3-methyl-n-butyl) indole (400 mg, 59%) as a yellow crystalline solid.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[CH2:11](Br)[CH:12]([CH3:14])[CH3:13]>>[CH3:11][CH:12]([CH3:14])[CH2:13][O:4][CH2:3][C:2]([CH3:10])([CH3:1])[CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C(O)C(C)(C)CO
Reactant: CC(C)CBr
Product: CC(C)COCC(C)(C)C(O)C(C)C
Yield: 88 %

Procedure:
Treatment of 2,2,4-trimethylpentan-1,3-diol with isobutyl bromide employing the alkylation reaction conditions described above provided 1-(2-methylpropyloxy)-2,2,4-trimethylpentan-3-ol in 88.0% yield (355.5 g, b.p.=81–82 C./2.5 mmHg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16](C3C=CC=CC=3Cl)[C:3]=12.[Cl:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)C(CC#N)=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:35]3[CH:34]=[CH:28][CH:27]=[C:26]([Cl:25])[CH:36]=3)[C:3]=12
Reactant: Cn1nc(-c2ccccc2Cl)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: N#CCC(=O)c1cccc(Cl)c1
Product: Cn1nc(-c2cccc(Cl)c2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound 13 was synthesised following similar procedures outlined in Example 1 (Compound 37), using 3-chlorobenzoylacetonitrile instead of 2-chlorobenzoyl acetonitrile in Step 1.
Reaction SMILES: [CH2:1]([O:3][C:4]12[CH2:11][O:10][CH2:9][CH:8]1[S:7][C:6]([NH:12][C:13]([C:15]13[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]4)[CH2:16]1)[CH2:22]3)=[O:14])=[N:5]2)[CH3:2].[CH3:25][O:26][CH2:27][CH2:28]Br>>[CH2:1]([O:3][C:4]12[CH2:11][O:10][CH2:9][CH:8]1[S:7]/[C:6](=[N:12]\[C:13]([C:15]13[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]4)[CH2:16]1)[CH2:22]3)=[O:14])/[N:5]2[CH2:28][CH2:27][O:26][CH3:25])[CH3:2]
Reactant: COCCBr
Reactant: CCOC12COCC1SC(NC(=O)C13CC4CC(CC(C4)C1)C3)=N2
Product: CCOC12COCC1S/C(=N\C(=O)C13CC4CC(CC(C4)C1)C3)N2CCOC

Procedure:
The product of Example 72C and 2-bromoethyl methyl ether were processed according to the method of Example 1B to afford the title compound. MS (ESI+) m/z 409 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][C:8]=2[C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:39]>C(Cl)Cl>[Br:39][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:9]=1
Reactant: OCc1ccc(C2CCCCC2)c(C(F)(F)F)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1cc(CBr)ccc1C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of (4-cyclohexyl-3-trifluoromethyl-phenyl)-methanol (300 mg, 1.16 mmol) and PPh3 (460 mg, 1.74 mmol) in DCM (5 mL) at 0° C. is added CBr4 (580 mg, 1.74 mmol) dissolved in DCM (2 mL). The reaction is stirred at 0° C. for 1 h followed by concentration. The residue obtained is purified by silica gel chromatography (5% EtOAc in hexanes) to give 4-bromomethyl-1-cyclohexyl-2-trifluoromethyl-benzene as a white solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:11]1(O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P(Cl)(Cl)(Cl)=O.Cl>O>[C:1]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4]
Reactant: O=C(O)c1ccccc1S
Reactant: Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Oc1ccccc1)c1ccccc1S
Reaction time: 0.5 h

Procedure:
In a 250 ml three-necked flask a mixture of 69.4 g (0.45 mol) of thiosalicylic acid and 42.3 g (0.45 mol) of phenol is melted at 135° C. with stirring. Then, at 125°-130° C., 24.5 g (0.16 mol) of phosphorus oxychloride are added dropwise, HCl being liberated. When the addition is complete (about 15 min.) stirring is carried out for 30 minutes. The resulting dark-brown clear solution is stirred into 500 ml of water, a brown oil separating. This oil is taken up in ethyl acetate. The organic phase is extracted three times by shaking with soda solution, washed with water, dried and concentrated to a residue. The residue, which still contains phenol, is purified by distillation. The crude product is recrystallised from 250 ml of absolute methanol in the presence of activated carbon. The product is obtained in the form of colourless crystals having a melting point of 89° C. The yield is 36.0 g (=35% of the theoretical amount).
Reaction SMILES: NC1C=C(C=CC=1)OC1C=CC(C2N=C(C3CCC3)N3C=CN=C(N)C=23)=CC=1.[CH:29]1([C:33]2[N:37]3[CH:38]=[CH:39][N:40]=[C:41]([NH2:42])[C:36]3=[C:35]([C:43]3[CH:48]=[CH:47][C:46]([O:49][C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=4[N+:56]([O-])=O)=[CH:45][CH:44]=3)[N:34]=2)[CH2:32][CH2:31][CH2:30]1>>[NH2:56][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[O:49][C:46]1[CH:47]=[CH:48][C:43]([C:35]2[N:34]=[C:33]([CH:29]3[CH2:30][CH2:31][CH2:32]3)[N:37]3[CH:38]=[CH:39][N:40]=[C:41]([NH2:42])[C:36]=23)=[CH:44][CH:45]=1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3ccc(Oc4ccccc4[N+](=O)[O-])cc3)c12
Agent: Nc1cccc(Oc2ccc(-c3nc(C4CCC4)n4ccnc(N)c34)cc2)c1
Product: Nc1ccccc1Oc1ccc(-c2nc(C3CCC3)n3ccnc(N)c23)cc1

Procedure:
Prepared according to a procedure analogous to that described for 1-[4-(3-aminophenoxy)-phenyl]-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine, except using 3-cyclobutyl-1-[4-(2-nitro-phenoxy)-phenyl]-imidazo[1,5-a]pyrazin-8-ylamine.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]([S:27]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=1)(=[O:29])=[O:28])[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19](=[O:22])[NH:20][CH3:21])[CH2:14][CH:13]2[C:23](OC)=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Cl:37][C:32]1[CH:31]=[C:30]([S:27]([N:9]([CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19](=[O:22])[NH:20][CH3:21])[CH2:14][CH:13]3[CH2:23][OH:24])(=[O:29])=[O:28])[CH:35]=[C:34]([Cl:36])[CH:33]=1
Reactant: CNC(=O)N1CC(C(=O)OC)c2cc(N(CC(=O)OC(C)(C)C)S(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(CO)c2cc(N(CC(=O)OC(C)(C)C)S(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
110 mg methyl 5-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-1-methylcarbamoyl-2,3-dihydro-1H-indole-3-carboxylate are dissolved in 3 ml of tetrahydrofuran, cooled to 0° C., combined with 4.2 mg lithium borohydride and stirred for 1 hour. Then the mixture is allowed to come up to ambient temperature and stirred overnight. Then it is divided between ethyl acetate and ice water, the pH is adjusted to 4 by the addition of citric acid and the phases are separated. The organic phase is washed with water and saturated sodium chloride solution, dried on magnesium sulphate and freed from the solvents in vacuo. The residue is chromatographed on silica gel (ethyl acetate).
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5](=[S:26])[NH:6][NH:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([CH3:23])[C:17]=1[Cl:24]>CO>[Cl:24][C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]1[NH:4][C:5](=[S:26])[NH:6][N:7]=1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)NNC(N)=S)c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(Cl)c(Nc2ccccc2-c2n[nH]c(=S)[nH]2)c1Cl
Reaction time: 8 h
Yield: 43.1 %

Procedure:
Sodium methoxide (734.0 mg, 13.59 mmol) is added to a solution of 2-[(2,6-dichloro-3-methylphenyl)amino]-benzoic acid, 2-(aminothioxomethyl)-hydrazide (1.466 g, 3.96 mmol) in 60 ml of methanol and the mixture is heated at reflux overnight, under a nitrogen atmosphere. An additional amount of sodium methoxide (702.0 mg, 13.00 mmol) is added and heating at reflux is continued overnight. The volatiles are removed in vacuo and the residue dissolved in water. The aqueous solution is acidified to pH 4-5 with 10% hydrochloric acid. The resultant white solid is collected, dissolved in tetrahydrofuran and chromatographed, eluting with hexane:ethyl acetate (1:2) to give 599.2 mg (43%) of 5-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione, mp 300°-305° C.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].C(N(CC)O)C.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:49])[C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([O:36][CH3:37])[C:30]=2[NH:38][C:39]([C:41]2[S:42][CH:43]=[C:44]([CH2:47]Cl)[C:45]=2[Cl:46])=[O:40])=[N:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>O.CN(C=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:49])[C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([O:36][CH3:37])[C:30]=2[NH:38][C:39]([C:41]2[S:42][CH:43]=[C:44]([CH2:47][N:1]3[C:12](=[O:13])[CH:11]4[CH:6]([N:7]=[CH:8][N:9]4[CH3:10])[N:4]([CH3:5])[C:2]3=[O:3])[C:45]=2[Cl:46])=[O:40])=[N:25][CH:26]=1
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CCl)c1Cl
Agent: CCN(O)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CN2C(=O)C3C(N=CN3C)N(C)C2=O)c1Cl
Temperature: 40 °C
Reaction time: 144 h

Procedure:
In a similar manner to that described in Paragraph F above, to a solution of theobromine (1.06 g, 5.9 mmol), N,N-diethylhydroxylamine (0.45 g, 5.0 mmol), N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (0.32 g, 0.6 mmol), and DMF (40 mL) was added K2CO3 (0.74 g, 5.3 mmol). The mixture was stirred at 40° C. for 6 days, then it was poured into water. The solid was isolated by filtration. Purification by recrystallization from CH2Cl2 and CH3OH afforded N-(5-chloropyridin-2-yl)-2-[((4-((2,3,4,5,6,7-hexahydro-3,7-dimethyl-2,6-dioxo-1H-purin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide, as a white solid; NMR (DMSO-d6) 10.90 (s, 1H), 9.40 (s, 1H), 8.36 (d, 1H), 8.12 (d, 1H), 8.06 (s, 1), 7.90 (dd, 1H), 7.55 (s, 1H), 7.38 (d, 1H), 7.27 (d, 1H), 4.97 (s, 2H), 3.90 (s, 6H), 3.40 (s, 3H), ppm.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:25]([CH2:30][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[S:26]([CH3:29])(=[O:28])=[O:27])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:20][CH:21]=[CH:22][N:23]=4)[C:8]=3[CH:24]=2)[CH2:3][CH2:2]1.[F:38][C:39]([F:54])([S:50](F)(=[O:52])=[O:51])[C:40]([F:49])([F:48])[C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:54][C:39]([F:38])([S:50]([O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:11][C:7]3[CH:6]=[C:5]([N:25]([CH2:30][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:35])=[O:36])[S:26]([CH3:29])(=[O:27])=[O:28])[C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:24][C:8]=3[C:9]=2[C:19]2[NH:23][CH:22]=[CH:21][N:20]=2)=[CH:13][CH:14]=1)(=[O:52])=[O:51])[C:40]([F:48])([F:49])[C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CS(=O)(=O)CCCCN(c1cc2oc(-c3ccc(O)cc3)c(-c3ncc[nH]3)c2cc1C1CC1)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCCCN(c1cc2oc(-c3ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc3)c(-c3ncc[nH]3)c2cc1C1CC1)S(C)(=O)=O
Yield: 95.4 %

Procedure:
A mixture of Example 168B (190 mg, 0.349 mmol) 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (116 mg, 0.384 mmol), and potassium carbonate (62.8 mg, 0.454 mmol) in N,N-dimethylformamide (3 mL) was stirred for 2 hours and partitioned with ethyl acetate and water. The organic layer was washed with brine twice, dried with sodium sulfate, filtered and concentrated. The resulting solid was triturated with hexane and filtered to give the title compound as a solid (275 mg, 95%). MS (ESI+) m/z 826 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=O)[C:11]([N:13]2[CH2:17][CH2:16][CH:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[CH2:14]2)=O)=[CH:2]1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:39]>CCOCC>[ClH:39].[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH:15]1[CH2:16][CH2:17][N:13]([CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:14]1
Reactant: COc1ccccc1OC1CCN(C(=O)C(=O)c2c[nH]c3ccccc23)C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1OC1CCN(CCc2c[nH]c3ccccc23)C1

Procedure:
A solution of 13.5 g. (0.037 mole) of 1 -(indole-3-ylglyoxyloyl)-3-(o-methoxyphenoxy)pyrrolidine in 50 ml. of anhydrous tetrahydrofuran was added dropwise to a stirred slurry of 7 g. (0.18 mole) of lithium aluminum hydride in 150 ml. of anhydrous tetrahydrofuran. The reaction mixture was worked up in the usual manner and the oily basic material which was isolated was dissolved in ether and treated with ethereal hydrogen chloride. The isolated hydrochloride weighed 10.7 g. (73%) and melted with decomposition (gas evolution) near a55° C. as a result of solvated ether. Thin layer chromatography of a sample of regenerated free base showed a single spot.
Reaction SMILES: [CH2:1]1[O:32][C:31]2[CH:30]=[CH:29][C:5]([CH2:6][N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)=[C:8]3[C:24]([O:26]CC)=[O:25])=[CH:4][C:3]=2[O:2]1.COC1C=CC(C2C3C(=CC=CC=3)NC=2C(OCC)=O)=CC=1.[H-].[Na+].C(Cl)C1C=CC2OCOC=2C=1>CN(P(N(C)C)(N(C)C)=O)C>[CH2:1]1[O:32][C:31]2[CH:30]=[CH:29][C:5]([CH2:6][N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]([C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)=[C:8]3[C:24]([OH:26])=[O:25])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)c2ccccc2n1Cc1ccc2c(c1)OCO2
Agent: CCOC(=O)c1[nH]c2ccccc2c1-c1ccc(OC)cc1
Agent: ClCc1ccc2c(c1)OCO2
Agent: [H-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc(-c2c(C(=O)O)n(Cc3ccc4c(c3)OCO4)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 66 %

Procedure:
Ethyl 1-(3,4-methylenedioxybenzyl)-3-(4-methoxyphenyl)indole-2-carboxylate. To a solution of ethyl 3-(4-methoxyphenyl)indole-2-carboxylate (110 mg, 0.37 mmol) in HMPA (2 mL) stirred at ice bath temperature under an argon atmosphere was added NaH (14 mg of 80% oil dispersion, 0.46 mmol, oil removed by pentane wash). After 15 min a solution of piperonyl chloride (128 mg, 0.75 mmol) in HMPA (0.5 mL) was added and the ice bath removed. The reaction mixture was stirred 7 h at room temperature then partitioned between 3N HCl (25 mL) and EtOAc (50 mL). The organic extract was washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (Na2SO4). The solvent was removed in vacuo. The residue was purified by chromatography (silica gel, gradient elution from 25% Et2O/hexanes to 45% Et2O/hexanes) to afford the title compound (105 mg, 66%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][C:22]([F:24])=[CH:21][CH:20]=3)[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: O=c1[nH]c2cc(F)ccc2c(=O)n1S(=O)(=O)c1ccc(Cl)cc1
Yield: 83.7 %

Procedure:
2.31 g (10.6 mmol) of 4-chlorobenzenesulfonylisocyanate and 1.50 g (9.67 mmol) of 2-amino-4-fluorobenzoic acid were treated in the same way as in Example 1 to obtain 2.87 g of the above-identified compound (yield 83.7%). Properties: colorless crystal, Melting point: >200° C., PMR (δppm, DMSO-d6): 6.86 (1H,d), 7.04 (1H,t), 7.76 (2H,d), 7.93 (1H,dd), 8.17 (2H,d), 11.65 (1H,br).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CBr>>[C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C=O)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CBr
Product: C=Cc1ccc(OC(C)=O)cc1

Procedure:
Polymer, 24, 995 (1983) discloses a method in which p-acetoxy benzaldehyde is subjected to the Wittig reaction where the compound is reacted to methyl bromide triphenylphosphine to obtain p-acetoxystyrene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH:12]([N:15](CC)C(C)C)(C)C.CN.O1CCCC1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:15][CH3:12])=[O:8]
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)c1cc(Br)ccc1C
Temperature: 2 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a solution of 5-bromo-2-methylbenzoic acid (2.325 mmol, 0.5 g) in dichloromethane (25 mL) under nitrogen was added N,N-diisopropylethylamine (0.75 g, 5.8 mmol). Reaction then cooled in an ice bath to 2° C. and the yellow solution treated with 2M methylamine in tetrahydrofuran (3.49 mL, 6.98 mmol) over 5 minutes, followed by 1-propanephosphonic acid cyclic anhydride as a 50% wt solution in ethyl acetate (2.08 mL, 3.49 mmol) added dropwise. The ice bath was then removed and stirring continued overnight. The mixture was purified on silica (15 g column on Isolera 4) eluting with 0-5% methanol in dichloromethane to afford 5-Bromo-N,2-dimethylbenzamide (0.5 g, 2.2 mmol).