Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:10]=2)[C:5](=[O:21])[N:4]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=2)[C:3]1=[O:32].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:28][CH2:27][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:4]2[C:5](=[O:21])[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([C:12]#[C:13][CH2:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:7]=3)[N:2]([CH3:1])[C:3]2=[O:32])=[CH:31][CH:30]=1
Reactant: Cn1c(=O)n(Cc2ccc(C(=O)Cl)cc2)c(=O)c2cc(C#CCc3ccccc3)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(Cc2ccc(CO)cc2)c(=O)c2cc(C#CCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.4 %

Procedure:
A solution of 0.5 g (1.1 mmol) of compound obtained in Example 19, Step 1 in 50 ml of tetrahydrofuran, was added dropwise to a suspension of 0.047 g (1.2 mmol) lithium aluminum hydride in 50 ml tetrahydrofuran at 0° C. After complete addition, the off-white suspension was warmed to room temperature and stirring was continued for 4 hours. The reaction mixture was concentrated in vacuum and carefully partitioned between 1 M HCl and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give an oily yellow solid. Chromatography (silica, 1:1 ethyl acetatelhexanes) gave 0.25 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[C:19]([F:26])=[CH:18][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]1=[O:17].CCN(C(C)C)C(C)C.[Cl:36][C:37]1[CH:42]=[N:41][C:40](Cl)=[CH:39][N:38]=1>CN(C=O)C.CCOC(C)=O>[Cl:36][C:37]1[N:38]=[CH:39][C:40]([N:14]2[CH2:15][CH2:16][CH:11]([N:7]3[CH2:8][CH2:9][CH2:10][C@H:5]([O:4][C:3]4[CH:18]=[C:19]([F:26])[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:21][C:2]=4[F:1])[C:6]3=[O:17])[CH2:12][CH2:13]2)=[N:41][CH:42]=1
Reactant: Clc1cnc(Cl)cn1
Reactant: CS(=O)(=O)c1cc(F)c(O[C@H]2CCCN(C3CCNCC3)C2=O)cc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cc(F)c(O[C@H]2CCCN(C3CCN(c4cnc(Cl)cn4)CC3)C2=O)cc1F
Yield: 3.9 %

Procedure:
A stirred solution of (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-[1,4′-bipiperidin]-2-one (Preparation G; 40 mg, 0.103 mmol), DIEA (90 μL, 0.515 mmol), and 2,5-dichloropyrazine (30.7 mg, 0.206 mmol) in DMF (1 mL) was heated at 100° C. in a sealed tube for 2 hours. The mixture was cooled, diluted with EtOAc (25 mL), washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc/DCM 4:1) to afford (S)-1′-(5-chloropyrazin-2-yl)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-[1,4′-bipiperidin]-2-one (2 mg, 0.004 mmol, 4% yield) as a white solid. Mass spectrum (apci) m/z=501.1 (M+H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[O:9][CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].O.Cl>C1COCC1>[C:1]1([NH:7][C:8]2[O:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1coc(Nc2ccccc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1coc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 2-(phenylamino)oxazole-4-carboxylate (1.64 g, 6.94 mmol) and lithiumhydroxide (332 mg, 13.88 mmol) in THF (23 ml)/water (11.5 ml) was stirred at rt for 4 hours. The reaction mixture was acidified with 2 N HCl and extracted with EA (2 x). The combined organic phases were dried over Na2SO4, filtered and evaporated under reduced pressure to afford the title product. HPLC/MS (Method G): RtG=1.41 min, MS (Method D) [M+H]+=204.9.
Reaction SMILES: [NH2:1][C:2]1[C:11](I)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15].CCN(CC)CC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1
Reactant: COC(=O)c1cc(I)c(N)cc1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#C[Si](C)(C)C)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of compound 70n (0.642 mmol, 200 mg), Cut (0.064 mmol, 12.2 mg) and Pd(PPh3)2Cl2 (0.064 mmol, 45 mg) in THF (2 mL) was added ethynyltrimethylsilane (0.963 mmol, 95 mg) followed by Et3N (7.19 mmol, 1 mL) under N2. The reaction mixture was stirred at room temperature for 1.5 h and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 70p.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:12]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([OH:20])[C:13]=3[S:14][C:8]=2[N:7]=[C:6]1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31]C)[C:22]=1[Br:33])[CH2:2][CH2:3][CH3:4].Br.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[Br:33][C:22]1[C:23]([OH:31])=[C:24]([O:29][CH3:30])[C:25]([O:27][CH3:28])=[CH:26][C:21]=1[C:6]1[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:10](=[O:11])[C:9]2[C:12]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([OH:20])[C:13]=3[S:14][C:8]=2[N:7]=1
Reactant: CCCCn1c(-c2cc(OC)c(OC)c(OC)c2Br)nc2sc3c(O)cc(C)cc3c2c1=O
Agent: Br
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCn1c(-c2cc(OC)c(OC)c(O)c2Br)nc2sc3c(O)cc(C)cc3c2c1=O

Procedure:
3-Butyl-2-(2-bromo-3,4,5-trimethoxyphenyl)-8-hydroxy-6-methyl-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one (compound No. 694) (40 mg) was stirred with HBr in acetic acid (1 ml) for five days. Saturated sodium sulphate solution was added and the product was extracted into ethyl acetate. After washing with water and brine, the solvent was evaporated and the precipitate was purified by chromatography using dichloromethane-methanol 99:1 as an eluent. Compound No. 696 was isolated as a by-product.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:23])([CH2:17][CH2:18]1)[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][CH2:10]2)[CH2:7][CH2:6]3.Cl.O.C(Cl)(Cl)[Cl:27]>C(Cl)Cl>[Cl:27][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:23])[C@H:9]3[CH2:10][CH:11]=[C:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1]
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Cl)C[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.33 h

Procedure:
2α,3α-Epoxy-5α-pregn-16-en-20-one (500 mg.) was dissolved in methylene chloride (15 ml.) and concentrated hydrochloric acid (12 ml.) was added. The mixture was shaken for 20 minutes, and then poured into water (100 ml.) and chloroform (100 ml.). The organic layer was separated, washed well with water, dried over sodium sulphate and evaporated to an oil. Recrystallisation from ethyl acetate gave title compound (447 mg.) as colourless crystals, m.p. 246°-252° , [α]D (c, 1.10)+ 65.8° , λmax. (EtOH) 239 nm (ε 8770).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:31])([F:30])[C:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=1)[CH2:16][C:13]1([C:12]([F:11])([F:30])[F:31])[CH2:14][CH2:15]1)=[O:6]
Reactant: O=C(O)c1ccccc1F
Reactant: NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1)c1ccccc1F

Procedure:
From 2-fluorobenzoic acid and 3-(1-trifluoromethyl-cyclopropyl)-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine. LCMS (MH+): m/z=435.1, tR (minutes, Method G)=2.58
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:38])([F:37])[F:36])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:36])([F:37])[F:38])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc2ncn(-c3cc(OCc4ccccc4C(F)(F)F)c(C(N)=O)s3)c2cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: NC(=O)c1sc(-n2cnc3cc(CO)ncc32)cc1OCc1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 9, 94 mg 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide (compound A2) and 53 mg of tetra-n-butylammonium fluoride solution (˜75% in H2O) in 6 ml tetrahydrofuran yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][C:5]([CH3:9])([CH2:7]O)[N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]N1C(=O)CCC1=O>ClCCl>[CH3:1][C:2]1[O:3][CH2:4][C:5]([CH3:9])([CH2:7][Br:29])[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=NC(C)(CO)CO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1=NC(C)(CBr)CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 40.1 g (310 mmol) of 2,4-dimethyl-4-hydroxymethyl-2-oxazoline (J. Nys and J. Libeer, Bull. Soco Chim. Belg., 65, 377 (1956)) and 85.5 g (326 mmol) of triphenylphosphine in 400 ml of dichloromethane is mixed at 0° C. in portions with 58.0 g (326 mmol) of N-bromosuccinimide and then stirred overnight at room temperature. The solution is concentrated by evaporation and the residue is pulverized with tert-butyl methyl ether. A precipitate develops, which is separated and washed with tert-butyl methyl ether. The combined filtrates are subjected to a fractionated distillation at normal pressure, and first the solvent is drawn off and then the title compound is distilled at an oil bath temperature of 200° C.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]1[CH2:12][C:13]([O:15]C)=[O:14].[OH-].[Na+]>C1COCC1>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)Cn1c(=O)ccc2ncccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cn1c(=O)ccc2ncccc21
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetate (0.205 g, 0.939 mmol) in THF (5 mL) was added sodium hydroxide (0.939 mL of a 3 N aqueous solution, 2.818 mmol) and the reaction mixture was stirred at 70° C. for 0.5 h. The resulting solution was concentrated under vacuum and co-evaporated from toluene to give 2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetic acid. Retention time (min)=1.033, method [3], MS(ESI) 205.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].Cl>O.C(Cl)Cl.C(N(CC)CC)C>[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1)=[O:23]
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=CCN(CC=C)c1nc(NC(=O)c2ccc(Cl)cc2Cl)n2oc(=O)nc2n1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
4.5 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are suspended in 100 ml. of methylene chloride and 10 ml. of triethylamine, cooled while stirring to about 5° C. and treated with 2.5 ml. of 2,4-dichlorobenzoyl chloride in 20 ml. of methylene chloride. After 1 hour at 0° C., the mixture is diluted with 100 ml. of water and adjusted to pH 4 with hydrochloric acid. The two phases are separated and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is chromatographed over silica gel using a mixture of chloroform and methanol (99:1) for the elution. Crystallization of the residue from chloroform and diethyl ether yields 2,4-dichloro-N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}benzamide having a melting point of 163°-164° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1.[CH2:27]([OH:30])[CH2:28][OH:29]>>[OH:29][CH2:28][CH2:27][O:30][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1
Reactant: CCCOc1ccc(CCl)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reactant: OCCO
Product: CCCOc1ccc(COCCO)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 45 %

Procedure:
This compound was prepared from 5-(5-chloromethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one and ethylene glycol following the procedure of Example 38 and was obtained as a white solid (45%), m.p. 101°-102° C. Found: C,63.13; H,6.88; N,13.98. C21H28N4O4 requires C,62.98; H,7.05; N,13.99%.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Br:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[Br:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][CH:60]1[CH2:65][CH2:64][N:63]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][N:10]=2)=[O:13])[CH2:62][CH2:61]1
Reactant: Brc1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Br)CC1)c1cc(-c2ccccc2)on1
Reaction time: 8 h
Yield: 22.3 %

Procedure:
To a stirred solution of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid (0.075 g, 0.00027 mol) in DMF (2 mL), was added DIPEA (171.5 mg, 0.00133 mol), HOBt (44.8 mg, 0.00033 mol) and EDCI.HCl (0.064 g, 0.00033 mol) at ambient temperature. After 2 minutes (2-bromo-phenyl)-piperidin-4-yl-amine dihydrochloride (0.078 g, 0.00026 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using basic aluminium oxide (35% ethyl acetate in hexane) to afford 0.028 g (22%) of 5-phenyl-isoxazole-3-carboxylic acid {2-[4-(2-bromo-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 483.1 (M+1)+, 97.4%, 1H NMR (DMSO-d6): δ 8.6 (t, 1H), 7.85 (m, 2H), 7.6 (m, 3H), 7.4 (m, 2H), 7.2 (t, 1H), 6.85 (d, 1H), 6.55 (t, 1H), 4.7 (d, 1H), 4.3 (d, 1H), 4.2 (d, 2H), 3.9 (d, 1H), 3.6 (m, 1H), 3.2 (m, 1H), 2.8 (m, 1H), 2.0 (t, 2H), 1.4 (m, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]([NH:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)(=[O:17])[CH3:16]>>[NH2:8][C:5]1[N:6]=[N:7][C:2]([C:23]2[CH:24]=[C:19]([NH:18][C:15](=[O:17])[CH3:16])[CH:20]=[CH:21][CH:22]=2)=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Product: CC(=O)Nc1cccc(-c2nnc(N)nc2-c2ccccc2)c1
Yield: 64.6 %

Procedure:
N-[3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]acetamide (59 mg, 62%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3-acetamidophenylboronic acid (61.5 mg, 0.344 mmol) according to the general procedure of Example 1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=2[Cl:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>CC(C)=O.CCOC(C)=O.[Zn]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[Cl:21])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Sc2ccc([N+](=O)[O-])cc2Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(Sc2ccc(N)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-(4-tert-butyl-phenylsulfanyl)-2-chloro-4-nitro-benzene was dissolved in acetone (15 mL), then saturated aqueous NH4Cl (5 mL) was added and the mixture was cooled to 0° C. Solid zinc powder (3.7 g, 56 mmol) was added in portions over 10 min with rapid stirring. The mixture was allowed to warm to rt and was stirred 3 h. The mixture was diluted with EtOAc (250 mL), dried, and filtered through Celite®. Removal of solvent gave a yellow residue, which was used without further purification. MS (ESI): mass calcd. for C16H18ClNS, 291.1; m/z found 292.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 7.33-7.21 (m, 3H), 6.95 (d, J=8.5, 2H), 6.77 (d, J=2.4, 1H), 6.55 (dd, J=8.4, 2.4, 1H), 5.80 (s, 2H), 1.22 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]3[CH:23]=[N:24][C:25]([N:28]4[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]4[CH3:34])=[N:26][CH:27]=3)[S:21][C:14]=12>>[CH3:34][C:29]1[N:28]([C:25]2[N:26]=[CH:27][C:22]([C:20]3[S:21][C:14]4[C:15](=[N:16][CH:17]=[CH:18][C:13]=4[NH:11][C:7]4[CH:8]=[C:9]5[C:4](=[CH:5][CH:6]=4)[NH:3][C:2]([CH3:1])=[CH:10]5)[CH:19]=3)=[CH:23][N:24]=2)[C:32]([CH3:33])=[CH:31][CH:30]=1
Reactant: Cc1ccc(C)n1-c1ncc(-c2cc3nccc(Cl)c3s2)cn1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cnc(-n6c(C)ccc6C)nc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-5-aminoindole and 7-chloro-2-[2-(2,5-dimethyl-pyrrol-1-yl)-pyrimidin-5-yl]-thieno[3,2-b]pyridine by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ9.18 (s, 2H), 8.17 (d, 1h), 7.80 (s, 1H), 7.37 (s, 1H), 7.34 (d, 1H), 6.98 (d, 1H), 6.62 (d, 1H), 6.17 (s, 1H), 5.83 (s, 1H), 2.47 (s, 3H), 2.33 (s, 6H); RP18-HPLC RT: 6.81 minutes; API MS: 451 (M+1).
Reaction SMILES: [O:1]1[CH2:23][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH3:24][NH:25][CH3:26]>C(O)C>[OH:1][CH:2]([CH2:23][N:25]([CH3:26])[CH3:24])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1
Reactant: CC1(C)CC(c2ccccc2)c2ccc(OCC3CO3)cc2O1
Reactant: CNC
Solvent: CCO
Product: CN(C)CC(O)COc1ccc2c(c1)OC(C)(C)CC2c1ccccc1
Yield: 97 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-phenylchroman (6.1g), anhydrous dimethylamine (15ml) and ethanol were left to stand at ambient temperature until tlc showed that reaction was complete (c. 2hrs.). Removal of the solvent in vacuo gave 7-(2-hydroxy-3-dimethylaminopropoxy)-2,2-dimethyl-4-phenylchroman (6.8g, 97%) isolated as the hydrochloride salt, m.p. 210-215°, from acetone-ethanol.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH:1][N:2]2[N:11]=[C:10]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:21])=[O:34])=[CH:28][CH:27]=1)(=[O:24])=[O:25]
Reactant: Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Product: CS(=O)(=O)c1ccc(CC(=O)Nn2nc(S(=O)(=O)c3ccccc3)c3ccccc3c2=O)cc1

Procedure:
The product from Example 68B and 2-(4-(methylsulfonyl)phenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.56 (d, J=8.2, 1H), 8.42-8.35 (m, 1H), 8.15-8.08 (m, 1H), 8.04-7.99 (m, 3H), 7.91 (d, J=8.3, 2H), 7.82-7.77 (m, 1H), 7.71-7.65 (m, 2H), 7.57 (d, J=8.3, 2H), 3.83 (s, 2H), 3.24 (s, 3H); MS (DCI+) M/Z 515 (M+NH4)+.
Reaction SMILES: [O:1]1[CH2:6]C[CH2:4][O:3][CH:2]1[C:7]1[N:11]([CH3:12])[C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=3[F:32])[CH:14]=2)=[N:9][CH:8]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C([O-])(O)=O.[Na+]>CO>[CH3:4][O:3][CH:2]([O:1][CH3:6])[C:7]1[N:11]([CH3:12])[C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=3[F:32])[CH:14]=2)=[N:9][CH:8]=1
Reactant: Cn1c(C2OCCCO2)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)n1C
Temperature: 25 °C
Yield: 73.9 %

Procedure:
To a solution of 41 (2.5 g, 5.48 mmol) in MeOH (200 mL) was added CSA (127 mg, 0.548 mmol) and the reaction mixture was heated to reflux for 5 hours. It was then cooled to RT and solid NaHCO3 was added. The mixture was filtered and the filtrate was concentrated to dryness. The residual solid was dissolved in DCM, washed with water, dried over Na2SO4, filtered and concentrated. The resultant solid was triturated with Et2O to afford 42 (1.8 g, 74% yield) which was used without any further purification. MS (m/z): 445.1 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[CH:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[S:1]1[C:5]([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:17])=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=Cc1ccccc1
Reactant: c1ccc2sccc2c1
Product: OC(c1ccccc1)c1cc2ccccc2s1

Procedure:
Using general procedure B, benzo[b]thiophene was reacted with benzaldehyde to give benzo[b]thiophen-2-yl-phenyl-methanol as a colorless solid. MS: 223.1 ([M+H—H2O]+).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:16]([OH:17])=[C:15]([C:18]([OH:20])=[O:19])[C:14]3[C:9](=[C:10](C4C=CC=CC=4)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.[Br:29]C1C=CC=C2C=1NC(=O)C2=O.C(OCC(=O)CC1C=CC(Cl)=CC=1)(=O)C>>[Br:29][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[C:7]([CH2:6][C:5]1[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:16]([OH:17])=[C:15]2[C:18]([OH:20])=[O:19]
Reactant: O=C1Nc2c(Br)cccc2C1=O
Reactant: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c(-c3ccccc3)cccc12
Agent: CC(=O)OCC(=O)Cc1ccc(Cl)cc1
Product: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c(Br)cccc12
Yield: 23 %

Procedure:
This compound was synthesized by the procedure described above for Compound 2, reacting 7-Bromo-1H-indole-2,3-dione (1.00 g, 4.42 mmol) with intermediate 2 (1.25 g, 5.53 mmol). The crude acid was purified as described above for Compound 3, then recrystallized from acetonitrile to give product as large, bright yellow crystals (Compound 9, 0.398 g, 23% yield): 1H NMR (400 MHz, DMSO-D6) δ 4.35 (s, 2H) 7.35 (m, 4H) 7.46 (dd, J=8.6, 7.6 Hz, 1H) 7.92 (dd, J=7.5, 1.1 Hz, 1H) 8.50 (dd, J=8.6, 1.3 Hz, 1H); HRMS (ESI/FTMS) calcd for C17H12BrClNO3 (MH+) 391.9684, found 391.9689. Anal. Calcd for C17H11BrClNO3: C, 52.00; H, 2.82; N, 3.57. Found: C, 51.72; H, 2.77; N, 3.53.