Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)[CH2:11][C@H:10]1[NH:28][C:29](=[O:44])[CH2:30][NH:31][C:32](=[O:43])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1)C1C=CC=CC=1.BrC[C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48].C(Br)C1C=CC=CC=1.C(NC(=O)[O-])C1C=CC=CC=1>CO.[Pd]>[CH3:27][O:26][C:23]1[N:22]=[CH:21][C:20]([N:17]2[CH2:16][CH2:15][CH:14]([N:12]3[CH2:11][C@@H:10]([NH:28][C:29](=[O:44])[CH2:30][NH:31][C:32](=[O:43])[C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:40])([F:42])[F:41])[CH:34]=4)[C@H:9]([O:8][CH2:1][C:47]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[O:48])[CH2:13]3)[CH2:19][CH2:18]2)=[CH:25][CH:24]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COc1ccc(N2CCC(N3C[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)[C@H](OCc4ccccc4)C3)CC2)cn1
Agent: [Pd]
Agent: BrCc1ccccc1
Agent: O=C([O-])NCc1ccccc1
Solvent: CO
Product: COc1ccc(N2CCC(N3C[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)[C@H](OCC(=O)OCc4ccccc4)C3)CC2)cn1

Procedure:
The title compound was synthesized in similar fashion to rel-N-[2-({(3R,4R)-4-(benzyloxy)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide, benzyl bromoacetate was substituted for benzyl bromide, as well as benzylcarbamate deprotection was accomplished with H2 gas (1 atm), 10% Palladium/Carbon in methanol, and was isolated as a white solid. 1H-NMR (CD3OD) δ: 1.17-1.25 (m, 1H), 1.50-1.67 (m, 2H), 1.80-1.94 (m, 2H), 2.13-2.25 (m, 1H), 2.44 (dd, J=10.5, 4.2 Hz, 1H), 2.61-2.74 (m, 3H), 2.84 (dd, J=9.9, 6.0 Hz, 1H), 3.25 (dd, J=10.2, 6.3 Hz, 1H), 3.35-3.46 (m, 3H), 3.85 (s, 3H), 3.82-3.93 (m, 1H), 4.05-4.14 (m, 3H), 4.18-4.29 (m, 3H), 5.11 (s, 2H), 6.63 (d, J=9.0 Hz, 1H), 6.74 (d, J=7.8 Hz, 1H), 7.20-7.38 (m, 5H), 7.51 (t, J=7.8 Hz, 1H), 7.70-7.75 (m, 2H), 7.96 (d, 7.8 Hz, 1H), 8.06 (s, 1H). MS m/z: 670 (M+1).
Reaction SMILES: CC1[N+]([CH2:7][C:8]2[CH:9]=[N:10][C:11]([CH3:15])=[N:12][C:13]=2[NH2:14])=CSC=1CCO.N1C=C2C(N=CN2)=NC=1.C(OP(O)(O)=O)[C@H]1[O:33][C@@H](/N=C(\N)/CNC=O)[C@H](O)[C@@H]1O.C1N=CN([C@@H]2O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]2O)C=1N>>[NH2:14][C:13]1[C:8]([CH2:7][OH:33])=[CH:9][N:10]=[C:11]([CH3:15])[N:12]=1
Reactant: Cc1ncc(C[n+]2csc(CCO)c2C)c(N)n1
Reactant: N/C(CNC=O)=N\[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: Nc1cncn1[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: c1ncc2[nH]cnc2n1
Product: Cc1ncc(CO)c(N)n1

Procedure:
The following reactions comprise the biosynthesis of thiamine: Thiamine biosynthesis begins with purine metabolism. From here AIR synthetase, the fifth step in the pathway catalyzes the conversion of 5′-phosphoribosyl-N-formylglycinamidine (FGAM) to 5′-phosphoribosyl-5-aminoimidazole (AIR). 4-Amino-5-hydroxymethyl-2-methylpyrimidine is then formed in a series of reactions.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]([O-])=[CH:4][CH:3]=1.[CH3:13][S:14]([O:17]S(C)(=O)=O)(=[O:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[CH3:13][S:14]([O:17][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:16])=[O:15]
Reactant: [O-][n+]1ccc(O)c2ccccc21
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)Oc1cnc2ccccc2c1O
Reaction time: 4 h

Procedure:
A mixture of 4-hydroxyquinoline-1-oxide (1 g), methanesulphonic anhydride (2 g) and potassium carbonate (2 g) in dichloromethane (20 ml) was stirred at 0° for 4 hours. Water (20 ml) was added to the mixture and the dichloromethane layer separated. The aqueous layer was extracted with dichloromethane (2×60 ml). The combined dichloromethane layer and extracts were dried over magnesium sulphate and evaporated to give a gum which was purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (19:1) to give the novel compound 4-hydroxyquinol-3-yl methanesulphonate, m.p. 224°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)=[O:10].[C:21]1([NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27].C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[NH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:28][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)=[O:10]
Reactant: O=C(CCCCCCCBr)c1ccc2ccccc2c1
Reactant: Nc1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccccc1NCCCCCCCC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.3 %

Procedure:
To a solution of 1-bromo-7-[(2-naphthoyl)]heptane 72 (62 mg, 0.17 mmol) in toluene (2 mL) and DMF (1 mL) was added 1,2-phenylenediamine (60 mg, 0.56 mmol) and N,N-diisopropylethylamine (36 μL, 0.21 mmol) and the reaction mixture was stirred at room temperature for 2 hours then at 75° C. for two hours and finally refluxed for 5 hours. Saturated sodium bicarbonate solution (5 mL) was added and the mixture was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with deionized water (20 mL), washed with brine (10 mL), and dried (MgSO4). The solvents were removed in vacuo and the title compound 73 (2 mg, 3%) was isolated by column chromatography (3:7-4:6 ethyl acetate:hexane) followed by recrystallization from ether and hexane. 1H NMR (400 MHz, DMSO-d6): δ 8.69 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.00 (m, 3H), 7.64 (m, 2H), 6.52 (m, 1H), 6.47 (m, 1H), 6.38 (m, 2H), 4.46 (s, 2H), 4.30 (m, 1H), 3.17 (t, J=7.4 Hz, 2H), 2.99 (m, 2H), 1.69 (m, 2H), 1.60 (m, 2H), 1.39 (m, 6H).
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH3:22])(=O)=O)(C)C.C[Li].[Cl:32][C:33]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:34]=1[CH:35]=[O:36]>O1CCCC1>[CH3:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]([CH:35]([C:34]2[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:33]=2[Cl:32])[OH:36])=[CH2:22])=[CH:24][CH:25]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC(=NNS(=O)(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C)c1ccc(C)cc1
Agent: [Li]C
Solvent: C1CCOC1
Product: C=C(c1ccc(C)cc1)C(O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(4-methylphenyl)ethanone-2,4,6-triisopropylbenzenesulfonylhydrazone (6.54 g) in tetrahydrofuran (80 ml) at -70° C. was dropwise added a solution of methyl lithium (25 ml, 1.3M in ether) while stirring and maintaining the temperature of the mixture below -60° C. After 10 minutes the reaction mixture was allowed to warm to room temperature. When evolution of nitrogen from the reaction mixture ceased, a solution of 2,4-dichlorobenzaldehyde (3.48 g) in tetrahydrofuran (10 ml) was rapidly added. After stirring for 1 hour at room temperature the reaction was quenched with a saturated aqueous ammonium chloride solution. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, washed with water, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield an oil. The oil was chromatographed on silica gel eluting with ethyl acetate-hexane (3:97) to yield α-[1-(4-methylphenyl)ethenyl]-2,4-dichlorobenzenemethanol δ (CDCl3): 1.86 (1H,d, J=5 Hz), 2.64-2.78 (1H, dd, J=13.5 Hz, J=10 Hz), 2.92-3.04 (1H,dd, J=15 Hz, J=5 Hz), 4.8 (1H,m), 5.38 (2H,d, J=6 Hz) and 7.16-7.5 (10H,m) as a yellow oil (2.1 g) having the formula: ##STR13##
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:55][C:56]1[CH:64]=[CH:63][C:59]([C:60](Cl)=[O:61])=[CH:58][CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:60](=[O:61])[C:59]2[CH:63]=[CH:64][C:56]([F:55])=[CH:57][CH:58]=2)[CH2:49][CH2:48]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2ccc(F)cc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 26 %

Procedure:
The desired compound was prepared according to the procedure of Example A20 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-fluorobenzoyl chloride as starting materials in 26% yield. LCMS for C31H30ClFNγO2 (M+H)+: m/z=586.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[CH3:13])=[C:4]([CH3:22])[N:3]=1.B(Br)(Br)Br.[OH-].[NH4+]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[CH3:13])=[C:4]([CH3:22])[N:3]=1
Reactant: COc1ccc(C(C)CCCc2c(C)nc(N)nc2N)cc1
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1nc(N)nc(N)c1CCCC(C)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 100.7 %

Procedure:
A stirred mixture of 5.2 grams (0.017 mole) of 2,4-diamino-5-[4-(4methoxyphenyl)pentyl]-6-methylpyrimidine in 200 mL of methylene chloride was cooled to about 0 ° C., and 52 mL (0.052 mole) of boron tribromide (1M in methylene chloride) was added dropwise during a 20 minute period while maintaining the reaction mixture temperature between -5° C. and +5 ° C. Upon completion of addition, the reaction was allowed to warm to ambient temperature as it stirred for about 18 hours. After this time the reaction mixture was poured into about 200 grams of ice. The mixture was made slightly basic with concentrated ammonium hydroxide and was stirred until the ice melted. A solid precipitate was collected by filtration and dried at 60° C., yielding 4.9 grams of 2,4-diamino-5-[4-(4-hydroxyphenyl)pentyl]-6-methylpyrimidin mp 197°-201° C., dec. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: I[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][NH:22][S:23]([NH2:26])(=[O:25])=[O:24])[O:12]1.[C:27]1([C:33]#[CH:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>CN(C=O)C.[Cu]I.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>[CH3:19][C:17]1([CH3:20])[O:16][C@H:15]2[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[CH2:34][CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:12][C@H:13]([CH2:21][NH:22][S:23]([NH2:26])(=[O:25])=[O:24])[C@H:14]2[O:18]1
Reactant: C#Cc1ccccc1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNS(N)(=O)=O)O[C@H]2n1cnc2c(I)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNS(N)(=O)=O)O[C@H]2n1cnc2c(CCc3ccccc3)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
To a solution of N-{[(3aR,4R,6R,6aR)-6-(6-iodo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl}sulfamide (0.14 g, 0.28 mmol) in DMF was added phenylacetylene (0.115 g, 1.13 mmol), CuI (10.6 mg, 0.056 mmol), DIPEA (98 μL, 0.56 mmol) and Pd(PPh3)2Cl2 (10 mg, 0.028 mmol) The solution was stirred for 1 h at r.t. and concentrated. The residue was taken up in DCM, washed with saturated aq EDTA.Na2 (3×20 mL), dried (Na2SO4) concentrated and purified by flash chromatography (20 to 60% EtOAc/DCM) to give the title compound (0.08 g, 60%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:4]([NH2:11])[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[N:24]=[C:23]([CH3:25])[C:22]([C:26](O)=[O:27])=[CH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:4]([NH:11][C:26]([C:22]2[C:23]([CH3:25])=[N:24][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=3)=[N:20][CH:21]=2)=[O:27])[CH:3]=1
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: Cc1cn(N)c2cnccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C)c2ccncc21
Reaction time: 1 h
Yield: 9.9 %

Procedure:
A mixture of 3-methyl-pyrrolo[2,3-c]pyridin-1-ylamine (224 mg, 1.53 mmol), 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (354 mg, 1.53 mmol), HATU (693 mg, 1.82 mmol) and DIPEA (593 mg, 4.59 mmol) in DMF (8 mL) is stirred at 1500 C. for 1 h. The reaction is quenched with water, extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-100% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (3-methyl-pyrrolo[2,3-c]pyridin-1-yl)-amide (55 mg). MS: 362 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.15 (s, 1H), 8.69 (s, 1H), 8.37 (d, 1H), 8.24 (s, 1H), 8.20 (d, 1H), 7.68 (d, 1H), 7.55 (q, 1H), 7.47 (s, 1H), 7.29 (t, 1H), 2.84(s, 3H), 2.39 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=O)[CH2:8][O:9][CH2:10][C:4]=2[CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:13]=[N:12][C:5]2[NH:6][CH2:7][CH2:8][O:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1COCc2cc(Br)cnc2N1
Solvent: C1CCOC1
Product: Brc1cnc2c(c1)COCCN2
Temperature: 0 °C
Reaction time: 18 h
Yield: 38.1 %

Procedure:
To a solution of 3-Bromo-5,9-dihydro-6-oxa-1,9-diazabenzocyclohepten-8-one (1.0 g, 4.13 mmol) in THF (40 mL) at 0° C. was added BH3 (30 mL of a 1.0 M solution in THF, 30.0 mmol). The solution was heated to reflux. After 18 h, the solution was cooled to 0° C. and the reaction quenched with H2O (2.5 mL). The mixture was concentrated and the resulting off-white solid was dissolved in MeOH (30 mL) and NaOH (15 mL of a 2 N solution). The mixture was heated at reflux for 4 h. The MeOH was removed under reduced pressure. The resulting precipitate was collected by filtration and washed with H2O (20 mL). The wJiite solid was dried to give the title compound (0.360 g, 38%). 1H NMR (300 MHz, DMSO-d6) δ8.06 (d, J=23 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 6.55 (br s, 1H), 4.47 (s, 2H), 3.74-3.70 (m, 2H), 3.16-3.12 (m, 2H); ESI MS m/z 229 (100%); 231 (100%) [C8H9BrN2O+H]+.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[CH:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)[N:25]=2)=[CH:20][CH:19]=1)=[C:16]=[S:17]>>[OH:4][CH2:3][CH:2]([NH:1][C:16]([NH:15][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:28]=[CH:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:37])[F:38])=[CH:31][CH:30]=3)[N:25]=2)=[CH:22][CH:23]=1)=[S:17])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:10]=1
Reactant: NC(CO)c1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-(trifluoromethyl)phenyl)ethanol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (0.250 g, 53%): ESIMS m/z 568 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([Cl:12])[C:3]=1[N+:13]([O-])=O.S([O-])([O-])(=O)=O.[Mg+2].[H][H]>[Pt].C(OCC)(=O)C>[NH2:13][C:3]1[C:4]([Cl:12])=[N:5][C:6]2[C:11]([C:2]=1[NH2:1])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: [H][H]
Reactant: Nc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: Nc1c(Cl)nc2ccccc2c1N

Procedure:
4-amino-2-chloro-3-nitroquinoline (5 g, 0.0224 mol) was combined with ethyl acetate (300 mL), magnesium sulfate (1 g), and 5% Pt/C (0.5 g). The mixture was hydrogenerated on a Parr apparatus until no further uptake of hydrogen was observed. The resulting mixture was filtered and the solvent was removed at reduced pressure to afford a tan solid product 3,4-diamino-2-chloroquinoline.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:22][C:23]1[N:28]2[N:29]=[CH:30][C:31]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([OH:41])([CH3:40])[CH3:39])=[N:36][CH:37]=3)=[C:27]2[N:26]=[C:25]([CH:42]2[CH2:48][CH:47]3[NH:49][CH:44]([CH2:45][CH2:46]3)[CH2:43]2)[C:24]=1I.[CH3:51][S:52]([O-:54])=[O:53].[Na+].CS(C)=O>[Cu]I>[NH2:22][C:23]1[N:28]2[N:29]=[CH:30][C:31]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([OH:41])([CH3:40])[CH3:39])=[N:36][CH:37]=3)=[C:27]2[N:26]=[C:25]([CH:42]2[CH2:48][CH:47]3[NH:49][CH:44]([CH2:45][CH2:46]3)[CH2:43]2)[C:24]=1[S:52]([CH3:51])(=[O:54])=[O:53]
Reactant: CC(C)(O)c1ccc(-c2cnn3c(N)c(I)c(C4CC5CCC(C4)N5)nc23)cn1
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC(C)(O)c1ccc(-c2cnn3c(N)c(S(C)(=O)=O)c(C4CC5CCC(C4)N5)nc23)cn1
Yield: 82.1 %

Procedure:
2-{5-[7-amino-5-(8-azabicyclo[3.2.1]oct-3-yl)-6-iodopyrazolo[1,5-a]pyrimidin-3-yl]pyridin-2-yl}propan-2-ol tris(trifluoroacetate) (salt) (0.720 g, 0.851 mmol), sodium methanesulfinate (306 mg, 2.55 mmol), and Copper(I) iodide (486 mg, 2.55 mmol) were dissolved/suspended in dry dimethyl sulfoxide (18 mL, 250 mmol) under a nitrogen atmosphere. The reaction was placed in an oil bath at 90° C. After mixing 15 min, HPLC showed the starting material to have been consumed and a mixture of the desired material:des-iodo material was observed. The reaction mixture was poured into a 7:3 mixture of sat'd NH4Cl:20% NH4OH (200 ml) and extracted 3×75 ml with 10% IPA in DCM. The combined organics were washed with brine, dried, filtered and evaporated to provide a yellow oil, which was purified by silica gel chromatography, eluted with 0-15% (10% NH4OH in MeOH) in chloroform to provide the desired material as a yellow solid (319 mg).
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH2:11])=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][C:15]=1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:11][C:7]1[C:6]2[C:2]([C:18]3[CH:17]=[CH:16][C:15]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[C:14]([O:13][CH3:12])[CH:19]=3)=[CH:3][O:4][C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Reactant: Nc1nccc2occ(Br)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2coc3ccnc(N)c23)ccc1NC(=O)OC(C)(C)C
Yield: 98.3 %

Procedure:
A mixture of 3-bromofuro[3,2-c]pyridin-4-amine (0.443 g, 2.1 mmol) in 1,2-dimethoxyethane (16 mL) and water (8 mL) was treated with tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (0.872 g, 2.5 mmol,), sodium carbonate (0.749 g, 7.1 mmol) and tetrakis triphenylphosphine palladium (0) (0.144 g, 0.12 mmol) at 80° C. for 18 hours. The organic solvent was removed in vacuo and the aqueous mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel using heptane/ethyl acetate (4:1) followed by ethyl acetate as an eluents to give the title compound (0.734 g, 85%) as a tan solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.07 (s, 1H), 7.96 (s, 1H), 7.87 (d, 1H), 7.84 (d, 1H), 7.14 (d, 1H), 7.05 (dd, 1H), 6.94 (d, 1H), 5.55-5.62 (bs, 2H), 3.87 (s, 3H), 1.48 (s, 9H); RP-HPLC (Conditions f) Rt 12.13 min.; MS: MH+ 356.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Na].[CH3:11][SH:12]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClC1C=CC=CC=1>[CH3:11][S:12][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CS
Reactant: N#Cc1ccccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na]
Solvent: Clc1ccccc1
Product: CSc1ccccc1C#N

Procedure:
2-Chlorobenzonitrile (27.5 g, 0.2 mol), monochlorobenzene (30.0 g), and a 50% by weight aqueous solution (1.0 g) of tetra-n-butyl ammonium bromide were placed in a 500-ml four-necked flask equipped with a stirrer, a thermometer, a dropping funnel, and a condenser under a nitrogen atmosphere to obtain a mixture. A 30% by weight aqueous solution (51.4 g) of sodium salt of methanethiol (0.22 mol) was added dropwise to the mixture at 60 to 65° C. over a period of 5 hours under stirring. After completion of the dropwise addition, the mixture was further allowed to react at the same temperature for 12 hours. By this operation, 2-(methylthio)benzonitrile was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(OC)=O>>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1
Agent: COC(=O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 11.12 and making non-critical variations using methyl 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoate to replace methyl 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate, 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoic acid was obtained (89%) as a colorless solid: mp 234-237° C. (water); 1H NMR (300 MHz, CDCl3) δ 12.94 (s, 1H), 7.93-7.86 (m, 2H), 7.46-7.40 (m, 2H), 7.26-7.19 (m, 1H), 7.18-7.13 (m, 1H), 7.04-6.92 (m, 2H), 6.50 (s, 1H), 6.12 (s, 1H), 5.07-4.90 (m, 2H), 4.80 (d, J=9.3 Hz, 1H), 4.65 (d, J=9.3 Hz, 1H), 4.19-4.03 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.3, 167.5, 155.2, 144.7, 142.6, 141.9, 138.3, 132.1, 130.5, 130.2, 129.3, 127.8, 124.2, 123.7, 121.6, 111.6, 109.8, 99.3, 79.9, 64.7, 64.1, 57.7, 43.4; MS (ES+) m/z 429.9 (M+1).