Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:17][C@@H:18]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:19]([F:29])([F:28])[O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:11][S:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)C>[CH:14]1([CH2:13][S:12][CH2:11][C@H:10]([NH:17][C@@H:18]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:19]([F:28])([F:29])[O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:9][OH:8])[CH2:16][CH2:15]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](CSCC1CC1)N[C@@H](c1ccc(F)cc1)C(F)(F)Oc1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC[C@H](CSCC1CC1)N[C@@H](c1ccc(F)cc1)C(F)(F)Oc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 50.2 %

Procedure:
To a solution of [2-(tert-butyldimethylsilanyloxy)-1(R)-cyclopropylmethylsulfanylmethyl-ethyl]-[2,2-difluoro-2-(4-fluorophenoxy)-1(S)-(4-fluorophenyl)ethyl]amine (1.06 g, 1.94 mmol) in dry THF (10 ml) at 0° C., a 1M solution of tetrabutylammonium fluoride (2.3 ml, 2.3 mmol) was added. After stirring for 3 h at 0° C., the reaction mixture was diluted with ethyl ether (20 ml) and washed with sat. ammonium chloride solution (20 ml), brine (10 ml) and dried over sodium sulfate. After removal of the solvent under vacuum, the crude was purified by flash chromatography using ethyl acetate/hexanes (2/8) as eluent to give 3-cyclopropylmethylsulfanyl-2(R)-[2,2-difluoro-2-(4-fluorophenoxy)-1(S)-(4-fluorophenyl)ethylamino]propan-1-ol as an oil (0.418 g, 74%).
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:12][CH2:11][C@@H:10]1[NH:20][C:21]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=2)[N:24]=1)=[O:22])=[O:7])(C)(C)C.Cl.[CH3:35][N:36]1[CH2:41][CH2:40][C:39]2[N:42]=[C:43](C([O-])=O)[S:44][C:38]=2[CH2:37]1.[Li+]>C(O)C>[ClH:33].[Cl:33][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([C:21]([NH:20][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:14][C@H:9]1[NH:8][C:6]([C:43]1[S:44][C:38]3[CH2:37][N:36]([CH3:35])[CH2:41][CH2:40][C:39]=3[N:42]=1)=[O:7])=[O:22])[CH:32]=[CH:31]2
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)c2ccc3cc(Cl)ccc3n2)[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)c3ccc4cc(Cl)ccc4n3)sc2C1

Procedure:
(1S,2R,4S)-N2-(tert-Butoxycarbonyl)-N1-[(6-chloroquinolin-2-yl)carbonyl]-4-(N,N-dimethyl-carbamoyl)-1,2-cyclohexanediamine was treated with a saturated ethanol solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([S:35]([Cl:38])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[ClH:38].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:35]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH3:27])[CH:30]=3)(=[O:37])=[O:36])=[C:3]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(C)(=O)=O)c2)CC1
Product: COc1cccc(S(=O)(=O)Nc2ccc(N3CCCNCC3)cc2NS(C)(=O)=O)c1
Product: Cl

Procedure:
The compound was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}methanesulfonamide and 3-methoxybenzenesulfonylchloride (94 mg, 0.455 mmol) to give 160 mg as a purple solid. M+1 455.2 Calcd 455.13.
Reaction SMILES: CN(C)[CH:3]=[O:4].FC(F)(F)S(O[C:12]1[CH:13]([CH3:25])[CH2:14][N:15]([C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:16][CH:17]=1)(=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:54][OH:55]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][CH:13]1[C:12]([C:54]([O:4][CH3:3])=[O:55])=[CH:17][CH2:16][N:15]([C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:14]1
Reactant: CN(C)C=O
Reactant: CO
Reactant: Cc1cccnc1N1CC=C(OS(=O)(=O)C(F)(F)F)C(C)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)C1=CCN(c2ncccc2C)CC1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 1:1 mixture of N,N-dimethylformamide: methanol saturated with CO, was added the product from Example 9C (5.29 g, 15.6 mmol), palladium (II) acetate (0.088 g, 0.39 mmol), triphenylphosphine (0.31 g, 1.2 mmol) and triethylamine (4.3 ml, 31 mmol). The reaction was stirred overnight at room temperature under a CO atmosphere. The mixture was then partitioned between water and ether and the organic layer was washed with brine then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (gradient elution, 0 to 30% diethyl ether-hexanes) to provide the title compound. MS (DCI/NH3) m/e 247 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[N:38]#[C:39][NH2:40]>>[C:39]([NH:40][C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:29]=[C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:31]=[C:2]([F:1])[CH:3]=3)=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1)#[N:38]
Reactant: N#CN
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: N#CNc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and cyanamide according to conditions described in general procedure C. 1H NMR (400 MHz, CDCl3) δ 3.21 (t, J=4.8 Hz, 4 H), 3.81 (t, J=5.2 Hz, 4 H), 6.34 (d, J=6.0 Hz, 1 H), 6.70 (d, J=12.0 Hz, 1H), 7.16-7.20 (m, 2 H), 7.32-7.46 (m, 4 H), 7.76-7.78 (s, 1 H), 7.86-7.89 (m 1 H), 8.05 (d, J=6.4 Hz, 1 H), 9.61 (s, 1 H).
Reaction SMILES: I[CH2:2][C:3]1([CH3:19])[O:18][C:6]2=[C:7]([CH3:17])[C:8]3[CH2:9][C:10]([CH3:16])([CH3:15])[NH:11][C:12]=3[C:13]([CH3:14])=[C:5]2[CH2:4]1.Cl.[CH3:21][N:22]([CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:21][N:22]([CH:32]1[CH2:37][CH2:36][N:35]([CH2:2][C:3]2([CH3:19])[O:18][C:6]3=[C:7]([CH3:17])[C:8]4[CH2:9][C:10]([CH3:16])([CH3:15])[NH:11][C:12]=4[C:13]([CH3:14])=[C:5]3[CH2:4]2)[CH2:34][CH2:33]1)[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1
Reactant: Cc1c2c(c(C)c3c1NC(C)(C)C3)OC(C)(CI)C2
Reactant: CN(c1nc2ccccc2s1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c2c(c(C)c3c1NC(C)(C)C3)OC(C)(CN1CCC(N(C)c3nc4ccccc4s3)CC1)C2
Temperature: 180 °C
Reaction time: 4.5 h
Yield: 47.1 %

Procedure:
A suspension of 3,5,6,7-tetrahydro-2-(iodomethyl)-2,4,6,6,8-pentamethyl-2H-furo[2,3-f]indole (372 mg, 1.00 mmol), N-methyl-N-(4-piperidinyl)-1,3-benzothiazole-2-amine hydrochloride (427 mg, 1.50 mmol) and potassium carbonate (485 mg, 3.51 mmol) in N,N-dimethylacetamide (2 ml) was stirred for 4.5 hours at 180° C. under nitrogen atmosphere. Water was added to the reaction mixture and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane:ethyl acetate=5:1) and crystallized from ethyl acetate-hexane to obtain 231 mg of the title compound.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=2[O:2]1.[C:14](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
A mixture of (3,4-methylenedioxyphenyl)acetic acid (4.64 g, 25.74 mMol) in dry DMF (40 mL), cesium carbonate (9.2 g, 25.74 mMol) and methyl iodide (3.7 g, 26.0 mMol) in dry DMF (40 mL) was stirred at room temperature for 3 h. At the end of this period, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with saturated NaHCO3, water, brine and then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to provide pure methyl (3,4-methylenedioxyphenyl)acetate as an oil (4.38 g).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.O[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][CH:18]([CH2:21][O:22][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCC(CO)CC2)nn1
Reactant: Oc1ccccc1C(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCCC1CC1)c1ccc(N2CCC(COc3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
To a stirred solution of 6-(4-hydroxymethylpiperidin-1-yl)pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.275 g, 0.90 mmol) in THF (10 mL) was added 2-hydroxybenzotrifluoride (0.178 g, 1.10 mmol), triphenylphosphine (0.289 g, 1.100 mmol) and diethyl azocarboxylate (0.5 mL, 1.10 mmol). The resulting mixture was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the obtained crude product was purified by column chromatography to yield the title compound in 40% yield (0.035 g). 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J=9.9 Hz, 2H), 7.54 (d, J=7.9 Hz, 1H), 7.47-7.42 (m, 1H), 6.99-6.92 (m, 3H), 4.57-4.53 (m, 2H), 3.89 (d, J=5.9 Hz, 2H), 3.56-3.49 (m, 2H), 3.11-3.02 (m, 2H), 2.25-2.15 (m, 1H), 2.01-1.97 (m, 2H), 1.52-1.41 (m, 2H), 1.27-1.20 (m, 2H), 0.75-0.68 (m, 1H), 0.47-0.41 (m, 2H), 0.09-0.05 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 163.3, 160.0, 156.7, 144.3, 133.3, 127.2, 127.1, 126.8, 125.5, 120.1, 112.5, 112.2, 72.6, 44.9, 39.6, 36.1, 34.6, 28.2, 8.7, 4.2. MS (ES+) m/z 449 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][N:17](C(OC(C)(C)C)=O)[CH:18]=3)[CH2:11][C@@H:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:9]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:8][C:7]=2[CH:37]=1)#[N:2].[SnH3]C1N=[CH:43][CH:42]=[CH:41][N:40]=1.[ClH:45].Cl.Cl.N1C=C(CN2C3C=CC(C4C=NC=CC=4)=CC=3CN(C(=O)C(F)(F)F)C(CC3C=CC=CC=3)C2)N=C1.C(C1C=CC2NC[C@@H](CC3C=CC=CC=3)N(C(=O)CC3C=CC=CC=3)CC=2C=1)#N>>[ClH:45].[ClH:45].[NH:17]1[CH:18]=[C:14]([CH2:13][N:12]2[C:6]3[CH:5]=[CH:4][C:3]([C:1]4[N:2]=[CH:43][CH:42]=[CH:41][N:40]=4)=[CH:37][C:7]=3[CH2:8][N:9]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:11]2)[N:15]=[CH:16]1
Reactant: [SnH3]c1ncccn1
Reactant: CC(C)(C)OC(=O)n1cnc(CN2C[C@@H](Cc3ccccc3)N(S(C)(=O)=O)Cc3cc(C#N)ccc32)c1
Agent: Cl
Agent: N#Cc1ccc2c(c1)CN(C(=O)Cc1ccccc1)[C@H](Cc1ccccc1)CN2
Agent: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Product: CS(=O)(=O)N1Cc2cc(-c3ncccn3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1

Procedure:
Example 332 was prepared as a yellow solid from Compound A of Example 231 and 2-stannylpyrimidine as described for Compound B of Example 231 and Compound C of Example 231. MS (M+H)+ 475.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:9]([CH3:48])[C:10]3[C:15]([C:16]=2[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:13]=[C:12]([C:22]([NH:24][C:25]2([C:29]4[N:33]([CH3:34])[C:32]5[CH:35]=[C:36](/[CH:39]=[CH:40]/[C:41]([O:43]CCCC)=[O:42])[CH:37]=[CH:38][C:31]=5[N:30]=4)[CH2:28][CH2:27][CH2:26]2)=[O:23])[CH:11]=3)=[N:6][CH:7]=1.CO.[OH-].[Na+].C(O)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:9]([CH3:48])[C:10]3[C:15]([C:16]=2[CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:14][CH:13]=[C:12]([C:22]([NH:24][C:25]2([C:29]4[N:33]([CH3:34])[C:32]5[CH:35]=[C:36](/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42])[CH:37]=[CH:38][C:31]=5[N:30]=4)[CH2:26][CH2:27][CH2:28]2)=[O:23])[CH:11]=3)=[N:6][CH:7]=1
Reactant: CCCCOC(=O)/C=C/c1ccc2nc(C3(NC(=O)c4ccc5c(C6CCCC6)c(-c6ncc(Br)cn6)n(C)c5c4)CCC3)n(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(C2(NC(=O)c3ccc4c(C5CCCC5)c(-c5ncc(Br)cn5)n(C)c4c3)CCC2)nc2ccc(/C=C/C(=O)O)cc21
Temperature: 66.5 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
To the suspension of (E)-butyl 3-(2-(1-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido)cyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate VII (489.0 g, 91.9 Wt %, 633.3 mmol) in THF (1298 g) and MeOH (387 g) was added 50% NaOH (82.7 g, 949.9 mmol), followed by rinse with water (978 g). The mixture was stirred between 65-68° C. for about 1 h for complete hydrolysis. The resulting solution was cooled to 35° C., and filtered through an in-line filter (0.5 micron), and rinsed with a pre-mixed solution of water (978 g) and MeOH (387 g). The solution was heated to 60±4° C., and acetic acid (41.4 g, 689 mmol) was added over 1 h while the mixture was well agitated. The resulting suspension was stirred at 60±4° C. for 0.5 h. Another portion of acetic acid (41.4 g, 689 mmol) was charged in 0.5 h, and batch was stirred at 60±4° C. for additional 0.5 h. The batch was cooled to 26±4° C. over 1 h and held for 1 h. The batch was filtered, rinsed with a premixed solution of water (1956 g) and MeOH (773.6 g), dried at 50° C. under vacuum to give (E)-3-(2-(1-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido)cyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylic acid (1) (419.0 g, 95% yield) with ≧99.0 A % (240 nm) and 94.1 Wt % by HPLC.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.P(Br)(Br)[Br:20]>C1(C)C=CC=CC=1.ClCCl>[Br:20][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[CH:8]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Temperature: 100 °C

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (900 mg) in toluene (20 mL) at 40° C. was added phosphorus tribromide (0.10 mL) and the reaction mixture was heated at 100° C. for 16 h. After cooling to room temperature, the reaction was diluted with dichloromethane (40 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (2×40 mL). The organic layer was dried (MgSO4) and reduced in vacuo to give 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[C:4](=[O:14])[C:3]=1C(OCC)=O.Cl>O1CCOCC1.C(OCC)(=O)C.O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])([CH3:13])[C:4](=[O:14])[CH:3]=1
Reactant: CCOC(=O)C1=C(O)c2ccccc2C(C)(C)C1=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)C=C(O)c2ccccc21
Temperature: 25 °C
Yield: 61.4 %

Procedure:
A solution of the product of Example 9E (2.25 g, 8.65 mmol) in dioxane (50 mL) was treated with 1 N HCl solution (60 mL) and the mixture was stirred at reflux for 6 hours, cooled to 25° C., diluted with ethyl acetate and water. The organic layer was washed with water (2×) and saturated sodium chloride solution (1×), dried (Na2SO4), filtered and concentrated in vacuo. The residue was triturated with ether and filtered. The solid was washed with 1:1 ether-hexane and dried to give the title compound (1.0 g, 61%). 1H NMR (300 MHz, DMSO-d6): δ 11.79, 11.59 (two s, 1 H), 7.91 (m, 1 H), 7.58 (m, 2 H), 7.38 (m, 1 H), 5.63 (s, 1 H), 1.48 (s, 3 H), 1.38 (s, 3 H).
Reaction SMILES: [S:1](Cl)([Cl:4])(=[O:3])=[O:2].C(Cl)Cl.[CH2:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN1C[CH2:42][C:26](=[C:27]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=C[C:33]3[C:28]2=CC=C[CH:32]=3)CC1>C(N(CC)CC)C>[ClH:4].[CH:33]1[C:28]2[CH2:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:27]=2[CH:26]=[CH:42][C:32]=1[S:1]([N:19]1[CH2:20][CH2:21][N:16]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:17][CH2:18]1)(=[O:3])=[O:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cl
Product: O=S(=O)(c1ccc2c(c1)Cc1ccccc1-2)N1CCN(Cc2ccccc2)CC1
Yield: 33 %

Procedure:
The title compound is prepared by adding to a stirred solution of the above sulfonyl chloride intermediate (4 g, 0.015 mol) in 50 mL of methylene chloride (2.7 g, 0.015 mol), 1-(benzyl)piperazine (2.7 g, 0.015 mol) and triethylamine (6 mL). The reactin mixture is stirred overnight and the methylene chloride layer is washed with water and dried over anhydrous Na2SO4. Evaporation of the methylene chloride under reduced pressure affords crude product which is purified by HPLC using silica gel column and ethyl acetate as the eluent. The desired fractions (Rf =0.8) are evaporated to give pure free base which is converted to the hydrochloride salt; m.p. 274°-275° C. (33% yield).
Reaction SMILES: C[C:2]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:12](NC(C)C)(C)C.[Li].[CH3:20][O:21][C:22](Cl)=[O:23]>C1COCC1>[C:2]1([C:9]([O:11][CH3:12])=[O:10])([C:22]([O:21][CH3:20])=[O:23])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)Cl
Reactant: CC(C)NC(C)C
Reactant: CC1(C(=O)O)CCCCCC1
Agent: [Li]
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)OC)CCCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl cycloheptanecarboxylic acid (8.0 g, 51.2 mmol) in THF (18 mL) was added dropwise to a solution of lithium diisopropylamine (8.3 g, 76.8 mmol) in THF (70 mL) at −78° C. After stirring for 1 h at the same temperature, a solution of methylchloroformate (7.26 g, 76.8 mmol) was added slowly and the mixture was allowed to warm to room temperature. After 18 h the reaction mixture was quenched with saturated aqueous NH4Cl solution (100 mL) and was extracted with EtOAc (100 mL×3). The combined organic layers were dried (MgSO4). After removal of the solvent under reduced pressure, purification by flash column chromatography using an eluting system of hexane/EtOAc (95:5) yielded the title compound as a clear, colorless liquid (7.8 g, 71%). MH+215.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24].O>C(O)(=O)C>[Br:1][C:12]1[CH:11]=[C:10]2[C:6]([C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:9]2)=[CH:5][C:4]=1[Cl:3]
Reactant: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1F
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1[nH]c2cc(Br)c(Cl)cc2c1-c1ccccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Add 1.0 ml of bromine to 4.6 g of ethyl 5-chloro-3-(2-fluorophenyl)indole-2-carboxylate in 250 ml of glacial acetic acid. Stir for 16 hours at room temperature, add water and collect the precipitate. Ws the precipitate with warm methanol. Collect the dry ethyl 6-bromo-5-chloro-3-(2-fluorophenyl)indole-2-carboxylate, m.p. 193°-194°.
Reaction SMILES: N#N.[S:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2O)[CH:5]=[CH:4]1.CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>CC(OC)(C)C.C(Cl)(Cl)Cl>[Cl:21][C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[CH:5]=[CH:4][S:3][C:11]=12
Reactant: Oc1ccnc2ccsc12
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: ClC(Cl)Cl
Product: Clc1ccnc2ccsc12

Procedure:
A 2-L, 3-neck, rb flask equipped with a mechanical overhead stirrer, a 250-mL addition funnel, and a thermocouple w/N2-inlet adapter was charged with thieno[3,2-b]pyridin-7-ol (144 g, 952 mmol), chloroform (700 mL) and anhydrous N,N-dimethylformamide (100 ml, 1297 mmol). The heterogeneous mixture was cooled in an ice bath with stirring, then oxalyl dichloride (166 ml, 1905 mmol) was added dropwise via the addition funnel. Towards the end of the addition, the exotherm had diminished so the remaining reagent was added more quickly, which resulted in rapid off-gassing and the eruption of a portion of the contents out of the vessel. Upon complete addition, the mixture was allowed to stir out for 2 h, at which point LC-MS analysis indicated only about 10% conversion to the desired product (71556-13-A). The ice bath was removed, and the mixture was heated to reflux with a mantle. The heterogeneous mixture quickly turned homogeneous upon reaching temperature, and LC-MS indicated complete conversion after 1 h @ reflux (71556-13-B). After standing at ambient temp over the weekend, an orange solid had formed from the dark brown supernate. The mixture was cooled in an ice bath, then diluted with MTBE (800 mL), resulting in the exothermic precipitation of copious amounts of a dense, mustard-brown solid. The solid was isolated by vacuum filtration and washed with MTBE until the filtrate was colorless to yield the solid and a cloudy, bright orange filtrate. The solid product was then carefully partitioned between DCM (1 L) and sat'd aq. NaHCO3 (1 L). The phases were mixed and the light brown aqueous layer was back extracted with DCM (500 mL). The combined organic layers were washed with sat'd brine, then dried over anhydrous Na2SO4. MTBE (500 mL) was added, then concentrated by about 200 mL, then hexane (500 mL) was added to form a dark brown precipitate. The mixture was further concentrated by 100 mL, then cooled in an ice bath. The mixture was then filtered and washed with hexane/MTBE (200 mL). The filtrate was then concentrated to dryness to yield the title compound as a light brown oil that crystallized to a dark rust colored, oily solid (97.7 g, 60.5% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5]([NH2:7])=O.C(N(CC)CC)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O>ClCCl>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5]#[N:7]
Reactant: COc1ccc(Cc2ccc(C(N)=O)cc2O)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cc2ccc(C#N)cc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of 3-hydroxy-4-(4-methoxybenzyl)benzamide (0.047 g) and triethylamine (0.30 mL) in dichloromethane (1.8 mL) was added trifluoromethanesulfonic anhydride (0.34 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/methanol=9/1) to give 3-hydroxy-4-(4-methoxybenzyl)benzonitrile (0.014 g).