Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]2[N:30]=[CH:29][NH:28][N:27]=2)=[C:4]([NH:7][C:8](=[O:25])[CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:24])[S:5][CH:6]=1.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34]O>>[Cl:1][C:2]1[C:3]([C:26]2[N:30]=[CH:29][N:28]([CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])[N:27]=2)=[C:4]([NH:7][C:8](=[O:25])[CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:24])[S:5][CH:6]=1
Reactant: CN(C)CCO
Reactant: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)ccc21)Nc1scc(Cl)c1-c1nc[nH]n1
Product: CN(C)CCn1cnc(-c2c(Cl)csc2NC(=O)Cn2c(=O)ccc3cc(C(F)(F)F)ccc32)n1

Procedure:
The title compound was prepared from N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide (125 mg, 275 umol) and 2-(dimethylamino)ethanol (311 mg, 3.49 mmol) using the procedures described in Example 1.76 except that the reaction was run at 60° C. (rather than 0° C.). The residue was purified by HPLC to yield N-(4-chloro-3-(1-(2-(dimethylamino)ethyl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide. Method [7] Retention time 4.40 min by HPLC (M+=525 and 527) and (M+Na=547 and 549). 1H NMR (300 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.28 (s, 1H), 8.22 (d, J=9.3 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.72 (d, J=8.7, 1H), 7.16 (s, 1H), 6.87 (d, J=9.3 Hz, 1H), 5.32 (s, 2H), 4.28 (t, J=6.0 Hz, 2H), 2.64 (t, J=6.0 Hz, 2H), 2.15 (s, 6H).
Reaction SMILES: [CH2:1]([CH2:7][C@@H:8]([SH:12])[CH2:9][CH2:10][SH:11])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].O.[OH-].[Na+].OS(O)(=O)=O>C1(C)C=CC=CC=1>[CH2:9]1[C@@H:8]([CH2:7][CH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[S:12][S:11][CH2:10]1
Reactant: O=C(O)CCCC[C@@H](S)CCS
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)CCCC[C@@H]1CCSS1

Procedure:
125.5 g of the dihydrolipoic acid solution are stirred in 5 l of completely deionized water in a 10 l round-bottomed flask, and the solution is adjusted to pH 8.5 using dilute sodium hydroxide solution and treated with catalytic amounts of Fe(III) sulfate solution. Air is introduced until the color lightens. After addition of 600 ml of toluene, the mixture is adjusted to pH 2 using H2SO4. The phases are separated and the water phase is extracted once with toluene. The combined toluene phases are concentrated to about 25% of the volume. The residue is treated with 600 ml of heptane, stirred under nitrogen and then forced through a filter loaded with silica gel. The filter is washed with toluene/heptane mixture.
Reaction SMILES: CN([CH:4]=[CH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16]C)=[O:14])=[CH:9][CH:8]=1)C.Cl.[CH2:20]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[NH:32])=[CH:29][CH:28]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C[O-].[Na+]>CO>[CH2:20]([O:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]2[N:33]=[CH:4][CH:5]=[C:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=3)[N:32]=2)=[CH:34][CH:35]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCOc1ccc(C(=N)N)cc1
Reactant: CCOC(=O)c1ccc(C(=O)C=CN(C)C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCCOc1ccc(-c2nccc(-c3ccc(C(=O)OC)cc3)n2)cc1
Yield: 52.1 %

Procedure:
To a suspension of 1-(N,N-dimethylamino)-2-(4-ethoxycarbonylbenzoyl)ethylene (0.742 g) and 4-n-hexyloxybenzamidine hydrochloride (0.847 g) in methanol (10 ml) was added 28% sodium methoxide in methanol (0.64 ml). The suspension was refluxed for 6 hours, and partitioned with ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with acetonitrile, collected by filtration and dried under reduced pressure to give Methyl 4-[2-(4-n-hexyloxyphenyl)pyrimidin-6-yl]benzoate (0.61 g).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH:20]1([CH2:26][NH:27][CH2:28][CH:29]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH2:36])[CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(OCC)(=O)C.C(OC(C)C)(C)C>>[CH:20]1([CH2:26][NH:27][CH2:28][CH:29]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH:36][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: NCCN1CCC(CNCC2CCCCC2)C1
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCC(CNCC3CCCCC3)C2)c2ccccc21
Yield: 19 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[[(cyclohexyl)methylamino]methyl]-pyrrolidin-1-yl]ethanamine in a yield of 19% of theory. Colourless crystals, m.p. 166°-167° C. (ethyl acetate/methanol 1/1 v/v).
Reaction SMILES: [CH2:1](N(CC)CC)C.B.Cl.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][NH2:26])[CH2:20][CH2:19]1>O1CCCC1.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:19][CH2:20][N:21]([CH2:24][C@H:25]([NH2:26])[CH3:1])[CH2:22][CH2:23]1
Reactant: CCN(CC)CC
Reactant: COc1ccccc1N1CCN(CCN)CC1
Agent: B
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(C[C@@H](C)N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The above mentioned (R)-{1-methyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-amino-propan-2-1-one hydrochloride (5.90 g, 19.7 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) at room temperature. Triethylamine (6.3 mL, 45 mmol) was added, followed by dropwise addition of a 1M solution of borane in tetrahydrofuran (77.5 mL, 45 mmol). The resulting mixture was refluxed for 18 hours. After cooling the reaction mixture to room temperature, ethyl acetate (60 mL) and 2N aqueous HCl were added and the resulting mixture was stirred at room temperature for one hour. The layers were separated and the aqueous layer was made basic by careful addition of 50% aqueous NaOH. The resulting basic mixture was extracted with three 50 mL portions of ethyl acetate. The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration on a rotary evaporator yielded 4.62 g (94%) of the desired of 2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethylamine as a colorless oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].C(N(CC)C(C)C)(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([CH2:13][CH2:14][O:15][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:9]1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 2 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (200 mg, 0.44 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.97 mmol) in dichloromethane (25 mL). Cool in a ice-bath. Add dropwise, methanesulfonyl chloride (0.066 g, 0.57 mmol). After 2 hours, extract with 1 M hydrochloric acid solution and 5% sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give the title compound: Rf=0.42 (silica gel, 6% methanol/dichloromethane); mp; 64.0-66.0° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21]OS(C)(=O)=O)[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:27]1([C@H:33]([NH2:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN1C(=O)CCC1>[C:4]1([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH:35][C@@H:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH3:34])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)OC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CN1CCCC1=O
Product: C[C@@H](NC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1)c1ccccc1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
Methanesulfonic acid (R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl ester (1.43 g, 3.7 mmol) and (R)-1-phenyl ethylamine (3 mL) were added to NMP (5 mL), and the reaction mixture was stirred for 18 hours at 110° C. The reaction mixture was cooled to room temperature, quenched by addition of water, and made basic to pH 14 by addition of 1M aqueous NaOH. The mixture was extracted with diethyl ether, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0-30% EtOAc/hexanes) to give 1.2 g of (R)-(7-benzenesulfonyl-chroman-2-ylmethyl)-((R)-1-phenyl-ethyl)-aminel, MS (M+H)=408.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[CH:33]=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1CCCCC1>CO>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2/[CH:33]=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2C=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 100 °C
Yield: 116.1 %

Procedure:
To a mixture of 6-chlorooxindole (4.58 g, 20 mmol) and 4-(4-bromo-2-formyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (10 g, 26 mmol) in methanol (50 mL) was added piperidine (2.56 mL, 26 mmol) dropwise. The mixture was then heated at 100° C. for 3 h. After cooled to 4° C., the mixture was filtered and the precipitate was collected, dried to give the title compound as a bright yellow solid (12.4 g, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:19][O:20][C:21]2[C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:24]([C:36](=[O:38])[CH3:37])=[C:23]([CH3:39])[CH:22]=2)[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:26]3[CH:25]=[C:24]([C:36](=[O:38])[CH3:37])[C:23]([CH3:39])=[CH:22][C:21]=3[O:20][CH2:19][CH:16]3[CH2:18][CH2:17]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Reactant: CC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)cc1C
Product: CCOC(=O)c1c[nH]c2c(-c3cc(C(C)=O)c(C)cc3OCC3CC3)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 1-[4-cyclopropylmethoxy-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethanone (example A47) the title compound is obtained as colorless solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[CH:30][CH:29]=[CH:28]2.[OH-].[Na+]>CN(C=O)C.CO>[N:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1Nc2ccccc2/C1=C(/Nc1ccc2ncccc2c1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-2-indolinone and 3 equivalents of 6-amino-quinoline in DMF followed by treatment with 1N sodium hydroxide solution in MeOH.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:37]O)[N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8].CC[N:41](C(C)C)C(C)C.N>CN(C=O)C.CO>[NH2:41][CH2:37][C:4]1[NH:5][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]3[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([Cl:27])[CH:20]=3)[C:12]=2[F:28])=[O:8])=[C:2]([Br:1])[N:3]=1
Reactant: C[Si](C)(C)CCOCn1c(CO)nc(Br)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reactant: CCN(C(C)C)C(C)C
Agent: N
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(CN)nc3Br)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.2 %

Procedure:
Ms-CI (0.023 ml, 0.30 mmol) was added to a solution of 4-bromo-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-(hydroxymethyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.097 g, 0.15 mmol) and DIEA (0.26 ml, 1.50 mmol) in DMF (1 ml) and the reaction mixture was stirred at room temperature for 1 h. Ammonia (1 ml of a 7M solution in methanol, 7.00 mmol) was added and stirring was continued overnight. Deprotection using similar procedures as that described herein and purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% NH4OH) provided the title compound (0.004 g, 5%) as an off-white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.32 (br. s., 1H), 7.56 (s, 1H), 7.33-7.45 (m, 2H), 7.28 (br. s., 1H), 7.21 (s, 1H), 4.65 (br. s., 2H), 4.19 (s, 2H). ES-LCMS: m/z 511.9, 513.9, 515.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:18]=1[C:19]([O:21]C)=[O:20]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:17]([NH:16][C:13]([C:11]2[S:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[O:15])=[C:18]([CH:23]=1)[C:19]([OH:21])=[O:20]
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)s1
Reactant: COC(=O)c1cc(Cl)ccc1N
Product: O=C(Nc1ccc(Cl)cc1C(=O)O)c1ccc(-c2ccc(F)cc2)s1
Yield: 47 %

Procedure:
Using the same method as in Example 3-(i), methyl 5-chloro-2-({[5-(4-fluorophenyl)thiophen-2-yl]carbonyl}amino)benzoate was obtained using 5-(4-fluorophenyl)thiophen-2-carboxylic acid and methyl 2-amino-5-chlorobenzoate. Thereafter, using the same method as in Example 3-(ii), the target 5-chloro-2-({[5-(4-fluorophenyl)thiophen-2-yl]carbonyl}amino)benzoic acid was obtained (yield: 47%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([CH3:32])[NH:27]1>>[CH3:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([CH3:32])[N:27]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: C[C@@H]1CCC[C@H](C)N1
Reactant: O=C(c1ccc(-c2ccc(OCCCCl)cc2)cc1)N1CCCC1
Product: C[C@@H]1CCC[C@H](C)N1CCCOc1ccc(-c2ccc(C(=O)N3CCCC3)cc2)cc1

Procedure:
The product from Example 11A and (2R,6S)-2,6-dimethylpiperidine were processed as described in Example 10F to provide the title compound.
Reaction SMILES: [Br-].[C:2](=[S:4])=[S:3].Br[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:7]#[N:8].O>C1COCC1>[CH3:6][C:9]1[CH:14]=[CH:13][C:12]([C:2]([S:4][CH:6]([C:7]#[N:8])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[S:3])=[CH:11][CH:10]=1
Reactant: S=C=S
Reactant: N#CC(Br)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=S)SC(C#N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 100 ml round bottom flask was added 10 ml 4-tolylmagiesium bromide (1.0M solution in ethyl ether) and diluted to 20 ml with anhydrous THF. 0.76 g carbon disulfide was added dropwise to this mixture and stirred for ½ h at room temperature. Then to the dark red solution was added 2 g α-bromobenzeneacetonitrile dropwise and the mixture stirred for another 2 h. Water was added to the mixture and the organic product was extracted with diethyl ether (3×50 ml), dried with magnesium sulfate overnight and filtered. After removal of solvent and column chromatography (5:2 mixture of hexane and ethyl ether), pure α-cyanobenzyl 4-methyldithiobenzoate was obtained as a red odorless solid (48% yield). Proton and carbon NMR spectra were consistent with the expected structure, CTA-CP-6.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10](/[CH:11]=[CH:12]/[C:13]2[N:21]([CH3:22])[C:20]3[C:19](=[O:23])[N:18]([CH2:24][CH3:25])[C:17](=[O:26])[N:16]([CH2:27][CH3:28])[C:15]=3[N:14]=2)=[CH:9][CH:8]=1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C)C=O>[N:31]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10](/[CH:11]=[CH:12]/[C:13]2[N:21]([CH3:22])[C:20]3[C:19](=[O:23])[N:18]([CH2:24][CH3:25])[C:17](=[O:26])[N:16]([CH2:27][CH3:28])[C:15]=3[N:14]=2)=[CH:9][CH:8]=1)=[N+:32]=[N-:33]
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCCCCBr)cc3)n2C)n(CC)c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCCCCN=[N+]=[N-])cc3)n2C)n(CC)c1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Compound 177 (235 mg, 0.49 mmol) obtained in Reference Example 116 was dissolved in 10 ml of dimethylformamide. To the solution was added 161 mg (2.48 mmol) of sodium azide, and the mixture was stirred at 80° C. for 3 hours. Water was added thereto under ice cooling and the deposited crystals, were collected by filtration. The collected crude crystals were dissolved in chloroform, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform), followed by recrystallization from hexane/ethyl acetate to give 216 mg (yield quant.) of Compound 178 as pale yellow grains.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:14][C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[CH:17][C:16]=1[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:26][C:16]3[CH:17]=[N:18][N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:15]=3[CH3:14])[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Cc1c(C=O)cnn1-c1ccccc1
Reactant: Clc1nccnc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1-c1ccccc1
Yield: 66.9 %

Procedure:
Stir together 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (1.6 g, 8.43 mmol) and 5-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (2.35 g, 12.6 mmol) in dry tetrahydrofuran (10 mL) at room temperature for 15 min., under nitrogen. Add sodium triacetoxyborohydride (2.68 g, 12.6 mmol) and stir reaction for 1 hr. Quench reaction mixture with saturated aq. sodium bicarbonate (50 mL), then extract with DCM (3×50 mL) and pass through an IST Phase Separator Frit®. Concentrate and purify (silica gel chromatography, eluting with 5:95 methanol:DCM) and concentrate all fractions containing product. Pass the mixture through a CBA column to retain the product, wash with methanol and then elute with 2 M ammonia in methanol. Recrystallize from hot ethanol and dry in vacuum oven to give 3′-chloro-4-(5-methyl-1-phenyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl as white crystals (2.08 g, 65%). MS (ES): m/z=369 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C([Li])CCC.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH2:28]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])[C:5]1[S:1][C:2]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[N:3][CH:4]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)Nc1nccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(NC(=O)OC(C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
A solution of tert-butyl thiazol-2-ylcarbamate (15.0 g, 75 mmol), in THF (200 mL) was stirred at −78° C. and then n-butyl lithium (63 mL, 157 mmol) was added dropwise over 15 minutes. The resulting solution was stirred at −78° C. for 30 minutes, and then tributyltin chloride (22 mL, 82 mmol) was then added dropwise. The resulting pale yellow mixture was stirred for 30 minutes at −78° C. The bath was then removed, and the mixture was allowed to warm to room temperature. The reaction was then stirred for 2.5 hours. The reaction mixture was quenched with a saturated NH4Cl solution (300 mL). The layers were separated, and the aqueous layer was extracted with ether (3×100 mL). The organic layers were combined, washed with brine (300 mL), dried over MgSO4, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (330 g), eluting with a gradient of 10% to 20% EtOAc in hexanes, to provide the title compound (30 g, 81%) LCMS (M+H+) 490.1 calc. for C20H38N2O2SSn 490.1; 1H NMR (400 MHz, CDCl3) δ ppm 7.31 (s, 1H), 1.59 (s, 9H), 1.30 (tt, 6H), 1.54 (t, 6H), 1.10 (qt, 6H), 0.80 (t, 9H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]1>>[CH3:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([N:34]3[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[CH2:32][C:33]3=[O:37])[CH:10]=2)[C:6]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:7]1=2
Reactant: O=C1CN(CCc2ccccn2)CCN1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccccn5)CC4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 17.7 %

Procedure:
tert-Butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (820 mg, 2.25 mmol) and 4-(2-(pyridin-2-yl)ethyl)piperazin-2-one (426 mg, 2.08 mmol) were reacted according to Example 2 (step f) to provide the title compound (180 mg, 16%) as a yellow oil: ESI MS m/z 490 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[C:3]([O:5][C:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[N:8][C:7]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[Br:27]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:27][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[N:10]([CH3:13])[C:11](=[O:12])[C:6]([O:5][C:3](=[O:4])[C:2]([CH3:26])([CH3:25])[CH3:1])=[C:7]([C:21]([O:23][CH3:24])=[O:22])[N:8]=2)=[CH:15][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1nc(-c2ccc(C)cc2)n(C)c(=O)c1OC(=O)C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(-c2ccc(CBr)cc2)n(C)c(=O)c1OC(=O)C(C)(C)C
Reaction time: 4 h

Procedure:
To a vigorously boiling solution of methyl 5-[(2,2-dimethylpropanoyl)oxy]-1-methyl-2-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate in carbon tetrachloride N-bromosuccinimide (1 eq.) and benzoyl peroxide (0.05 eq.) were added as dry powders. After 4 hr the mixture was allowed to reach room temperature and the precipitated succinimide was filtered off. The filtrate was evaporated under vacuum and the solid residue was used as such.