Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:29][C:28]2[CH:27]=[CH:26][C:5]([C:6]([CH2:8][N:9]3[CH2:14][CH2:13][CH:12]([N:15]4[CH2:20][C:19]5[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=5[O:17][C:16]4=[O:25])[CH2:11][CH2:10]3)=[O:7])=[CH:4][C:3]=2[O:2]1.[BH4-].[Na+]>CO>[CH2:1]1[O:29][C:28]2[CH:27]=[CH:26][C:5]([CH:6]([OH:7])[CH2:8][N:9]3[CH2:14][CH2:13][CH:12]([N:15]4[CH2:20][C:19]5[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=5[O:17][C:16]4=[O:25])[CH2:11][CH2:10]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C(CN1CCC(N2Cc3ccccc3OC2=O)CC1)c1ccc2c(c1)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1Oc2ccccc2CN1C1CCN(CC(O)c2ccc3c(c2)OCO3)CC1
Reaction time: 3 h
Yield: 82.6 %

Procedure:
In this example, 3.0 g of 1-(3,4-methylenedioxybenzoylmethyl)-4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)piperidine obtained in Example 2 is mixed with 150 ml of methanol. While the mixture is stirred at 0° to 10° C., 0.8 g of sodium borohydride is added thereto over a period of 3 hours. Then, the mixture is stirred overnight at room temperature. The mixture is further mixed with 0.4 g of sodium borohydride and stirred at room temperature for 3 hours. The white crystals deposited are separated by filtration, washed with methanol and water and dried to obtain 2.36 g of a crude product. In the meantime, the filtrate is concentrated under reduced pressure. The residue is mixed with water. The crystals deposited are separated by filtration, washed with water and dried to obtain 0.37 g of a crude product. The two crude products are combined and recrystallized from ethanol to obtain 2.49 g of the desired product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:34]([O:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([OH:52])[CH:43]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:53]1([CH3:62])[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[CH:59](O)[CH3:60]>C1COCC1>[CH2:34]([O:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([O:52][CH:59]([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[CH3:62])[CH3:60])[CH:43]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Cc1ccccc1C(C)O
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2ccccc2)cc1OC(C)c1ccccc1C
Reaction time: 0.25 h
Yield: 72.1 %

Procedure:
A solution of triphenylphosphine(5.48 g) in dry THF (35 mL) is treated with diisopropyl azodicarboxylate (4.23 g) at 0-5° C. and stirred for 15 minutes. The suspension is treated dropwise with a solution of methyl 4-benzyloxy-2-hydroxybenzoate (2.7 g) and 1-o-tolylethanol (1.42 g) in dry THF (35 mL) during 25 minutes at 0-5° C. and then stirred at 0-5° C. for 1 hour and at 25° C. for 24 hours. The mixture is evaporated and the residual gum purified by flash chromatography on silica, eluting with dichloromethane. Fractions homogeneous in the required product are combined and evaporated to yield methyl 4-benzyloxy-2-(1-o-tolyiethoxy)benzoate as a colourless oil (2.83 g, 72%). 1H NMR (CDCl3) 1.6(3H,d), 2.4(3H,s), 3.9(3H,s), 4.9(2H,s), 5.5(1H,q), 6.3(1H,s), 6.5(1H,d), 7.1-7.6(9H,m), 7.8(1H,d).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)=[CH:26][CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.N1C=CC(COC#CC2C=CC=CC=2)=C[CH:38]=1>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([O:30][CH2:31][C:36]5[CH:35]=[CH:34][N:33]=[CH:32][CH:38]=5)=[CH:28][CH:29]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:15])([F:17])[F:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(n2cc(-c3ccc(Oc4cccnc4)cc3)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Reactant: C(#Cc1ccccc1)OCc1ccncc1
Product: O=C1C(n2cc(-c3ccc(OCc4ccncc4)cc3)nn2)CCc2c(F)cccc2N1CC(F)(F)F

Procedure:
Prepared as for 6-fluoro-3-{4-[4-(pyridin-3-yloxy)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one, using 4-(pyridine-4-ylmethoxy)ethynylbenzene as the alkyne.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]2([NH:33]C(=O)C)[CH2:30][O:29]C(C)(C)[O:27][CH2:26]2)=[CH:19][CH:18]=1.[ClH:37]>C(O)C>[ClH:37].[NH2:33][C:25]([CH2:24][CH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:3]2[CH:4]=[CH:5][C:6]([S:8][C:9]3[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)=[CH:7][C:2]=2[F:1])=[CH:22][CH:21]=1)([CH2:30][OH:29])[CH2:26][OH:27]
Reactant: COc1ccc(Sc2ccc(-c3ccc(CCC4(NC(C)=O)COC(C)(C)OC4)cc3)c(F)c2)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(Sc2ccc(-c3ccc(CCC(N)(CO)CO)cc3)c(F)c2)cc1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
N-(5-{2-[2′-Fluoro-4′-(4-methoxyphenylthio)biphenyl-4-yl]ethyl}-2,2-dimethyl-1,3-dioxan-5-yl)acetamide (0.22 g) was dissolved in ethanol (4 mL), concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at 75° C. for 4 hr. The reaction mixture was concentrated to dryness, and the residual solid was suspended in ethyl acetate and collected by filtration to give the title compound (39 mg) as brown crystals.
Reaction SMILES: [NH2:1][CH:2]([CH3:9])[CH2:3][NH:4][CH2:5][CH:6]([NH2:8])[CH3:7].[C:10](=S)=S.S>CC1C2C(=CC=CC=2)C=CC=1>[CH3:9][CH:2]1[CH2:3][N:4]2[CH2:5][CH:6]([CH3:7])[N:8]=[C:10]2[NH:1]1
Reactant: CC(N)CNCC(C)N
Reactant: S=C=S
Agent: S
Solvent: Cc1cccc2ccccc12
Product: CC1CN2CC(C)NC2=N1
Temperature: 200 °C
Reaction time: 3 h

Procedure:
In a 100 mL flask, 0.4078 g of di-(2-aminopropyl)amine (0.00311 mol) was dissolved in 50 mL of 1-methylnaphthalene. Carbon disulfide (0.18 mL, 0.00298 mol) was added. The reaction was stirred for three hours then heated to 200° C. The reaction was heated for four days until production of hydrogen sulfide stopped. The solvent was then removed by distillation. The product was then dissolved in approximately 5 mL of hexanes and 0.5 mL of a 2.0 M ether solution of hydrogen chloride was added. The yield of the precipitate was 0.278 g (53%). The NMR had a doublet at 1.19 ppm, a multiplet at 3.44 ppm, a multiplet at 3.92 ppm and a multiplet at 4.15 ppm.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:67])[C@@H:22]([NH:56]C(OCC1C=CC=CC=1)=O)[CH2:23][S:24][CH2:25][C@H:26]([O:42][C:43](=[O:55])[NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:27][O:28][C:29](=[O:41])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>C(Cl)Cl>[NH2:56][C@@H:22]([CH2:23][S:24][CH2:25][C@H:26]([O:42][C:43](=[O:55])[NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:27][O:28][C:29](=[O:41])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:21](=[O:67])[NH:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8]
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)NCCCCCCCCCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(O)O)OC(=O)NCCCCCCCCCC
Temperature: 32 °C
Reaction time: 8 h

Procedure:
To a solution of (14R,18R)-14-(benzyloxycarbonylamino)-18-(decylcarbamoyloxy)-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12,22-diazadotriacontylphosphonic acid diethyl ester (1 eq) in DCM at 0° C. (0.1 M) was added trimethylsilyl bromide (10 eq). The reaction mixture was stirred at 32° C. overnight then cooled to room temperature, diluted with DCM and concentrated. The crude material was dried under high vacuum for 2 hours then purified by reverse phase high performance liquid chromatography (HPLC) with a C4 column eluting with a gradient of 40-100% MeCN/10 mM NH4OAc (95:5) in 10 mM NH4OAc (pH 9) to afford (14R,18R)-14-amino-18-(decylcarbamoyloxy)-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12,22-diazadotriacontylphosphonic acid as a white solid. 1H NMR (DMSO-d6): δ 8.49 (t, 1H), 7.32 (m, 2H), 4.78 (m, 1H), 4.01 (m, 2H), 3.0-3.6 (m, 18H), 2.88 (m, 4H), 2.52-2.81 (m, 5H), 1.54 (m, 2H), 1.34 (m, 4H), 1.12-1.24 (m, 28H), 0.81 (t, 6H). LRMS [M+H]=801.5.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:40][CH:41]([CH3:43])[CH3:42])=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([O:40][CH:41]([CH3:42])[CH3:43])=[C:33]4[C:37]=3[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CC(C)Oc1ccc(N)c2c1CN(C)C2=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(OC(C)C)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 7-Amino-2-methyl-4-(propan-2-yloxy)-2,3-dihydro-1H-isoindol-1-one (Compound 207A). MS (ES+): m/z 608.27 (100) [MH+]; HPLC: tR=1.18 min (UPLC, purity).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.C([O-])([O-])=O.[Na+].[Na+]>>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3cccc(C(F)(F)F)c3)CC2)cc1
Yield: 103.2 %

Procedure:
The title compound (D26) (76 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-methyl 4-(1-(piperidine-2-carboxamido)cyclopropyl)benzoate (D13) (50 mg, 0.16 mmol) and 3-(trifluoromethyl)benzyl bromide (0.038 ml, 0.25 mmol). (Na2CO3: 2.5 eq; reaction time: 6 hrs; 60° C.)
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([CH3:13])=[CH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]>O1CCCC1>[N+:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:3][C:4]1[S:5][C:6]([CH3:13])=[CH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-:23])=[O:22]
Reactant: COC(=O)c1cc(C)sc1N
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)sc1Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred suspension of sodium hydride (2 g) in dry tetrahydrofuran (25 mL) under a nitrogen atmosphere was added a solution of methyl 2-amino-5-methylthiophene-3-carboxy-late (4.8 g, 0.028 mol) and 2-fluoronitrobenzene (4.0 g, 0.025 mol) in dry tetrahydrofuran (30 mL). The mixture was stirred at 25° C. for 20 hours, poured onto ice and partitioned between 2N hydrochloric acid and ethyl acetate. The organic extracts were dried over magnesium sulfate, the solvent was evaporated under reduced pressure and the title compound purified by chromatography on silica gel, eluted with toluene, and crystallized from ethanol (4.1 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[K+].F[C:11]1[CH:12]=[CH:13][C:14]2[S:15](=[O:26])(=[O:25])[C:16]3[C:21]([O:22][C:23]=2[CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3>CN(C)C=O>[F:1][C:2]([F:7])([F:6])[CH:3]([CH3:4])[O:5][C:11]1[CH:12]=[CH:13][C:14]2[S:15](=[O:25])(=[O:26])[C:16]3[C:21]([O:22][C:23]=2[CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3
Reactant: CC(O)C(F)(F)F
Reactant: O=S1(=O)c2ccccc2Oc2cc(F)ccc21
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc2c(c1)Oc1ccccc1S2(=O)=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
(rac)-1,1,1-Trifluoro-2-propanol (Oakwood) (0.45 g, 0.004 mole) was added to a stirred, ice-bath cooled mixture of potassium hydride (approximate 50% dispersion in mineral oil) (Aldrich) (0.32 g, 0.004 mole) and N,N-dimethylformamide (50 mL). The ice-bath was removed, and the reaction was stirred at ambient temperature for 1 hour. 3-Fluorophenoxathiin 10,10-dioxide (Example 47) (1.00 g, 0.004 mole) was added, and the mixture was heated at reflux under nitrogen for 2 hours. The reaction was cooled, and the volatiles were removed by spin evaporation in vacuo. The residue was purified by column chromatography on Silica Gel 60 using ethyl acetate-hexanes:3-7. The appropriate column fractions were combined, and the volatiles were removed by spin evaporation in vacuo to give 1.21 g (87% yield) of (rac)-3-(2,2,2-trifluoro-1-methylethoxy)phenoxathiin 10,10-dioxide. Recrystallization from ethanol gave 1.03 g (74yield) of the analytical sample, m.p. 97-98.5° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:11]=O)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.CC(O)C.[NH2:17][C:18]1[CH:27]=[CH:26][C:21]2[NH:22][C:23](=[O:25])[NH:24][C:20]=2[CH:19]=1>C(O)(=O)C>[Br:1][C:2]1[C:3](/[CH:11]=[N:17]/[C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23](=[O:25])[NH:24][C:20]=3[CH:19]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Reactant: O=Cc1cc2c(cc1Br)OCO2
Solvent: CC(=O)O
Solvent: CC(C)O
Product: O=c1[nH]c2ccc(/N=C/c3cc4c(cc3Br)OCO4)cc2[nH]1
Yield: 95 %

Procedure:
6-bromobenzo[d][1,3]dioxol-5-carbaldehyde (0.63 g, 1.31 mmol), IPA (6 ml), and 5-amino-1H-benzo[d]imidazole-2(3H)-one (0.2 g, 1.31 mmol) were put in a 25 ml flask, and acetic acid (10 ml) was slowly added dropwise thereto while the mixture was stirred under nitrogen charging conditions, followed by stirring for 12 hours under reflux conditions. After that, the temperature of the mixture was lowered to room temperature, and the thus obtained solid was washed with methylene chloride and methanol, followed by filtering, thereby obtaining clean (E)-5-((6bromobenzo[d][1,3]dioxol-5-yl)methyleneamino)-1H-benzo[d]imidazole-2(3H)-one at 95% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].C(=O)([O-])[O-].[K+].[K+]>C(OC(=O)C)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:9])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1ccccc1Oc1ccc(Cl)nn1
Temperature: 160 °C
Reaction time: 6 h
Yield: 56.7 %

Procedure:
A mixture of 278.7 g (1.87 mol) of 3,6-dichloro-pyridazine, 202.3 g (1.87 mol) of 2-methylphenol and 259 g (1.87 mol) of potassium carbonate was stirred at 160° C. for 6 hours. The reaction mixture was cooled to 70° C. and 2 L of ethyl-acetate was added. This mixture was washed successively with 1 mol/L sodium hydroxide aqueous solution (4×500 mL), water (4×500 mL) and brine (50 mL), and dried over anhydrous magnesium sulfate. The solvent was removed, and isopropyl ether was added to the residue to form crystal. The crystal was collected by filtration to obtain 234.2 g (1.06 mol, Yield: 56.7%) of 3-chloro-6-(2-methyl-phenoxy)pyridazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][C:24]#[CH:25])[CH3:21].C(N(CC)CC)C>[Cu]I.C1COCC1>[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][C:24]#[C:25][C:16]1[S:17][C:10]2[C:11](=[N:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:19])=[CH:3][C:2]=2[F:1])[CH:15]=1)[CH3:21]
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: C#CCN(CC)CC
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Temperature: 40 °C
Yield: 84.8 %

Procedure:
A stirred mixture of 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (965 mg, 2.50 mmol), N,N-diethylprop-2-yn-1-amine (417 mg, 3.75 mmol), copper(I) iodide (24 mg, 0.125 mmol), triethylamine (8.7 mL, 63 mmol), and THF (20 mL) was sparged with N2 for 5 minutes, then tetrakis(triphenyl -phosphine)palladium(0) (144 mg, 0.125 mmol) was added. The sealed reaction was heated to 40° C. for 18 hours. The mixture was concentrated, and then purified by Biotage Flash 40M silica gel chromatography system, eluting with EtOAc followed by 5% MeOH in EtOAc. The product was obtained as a waxy solid (783 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=6 Hz, 1H), 7.59 (s, 1H), 7.03 (t, J=9 Hz, 1H), 6.53 (m, 3H), 3.86 (br s, 2H), 3.78 (s, 2H), 2.73 (q, J=7 Hz, 4H), 1.19 (t, J=7 Hz, 6H). LRMS (ESI pos) m/e 370 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2C[CH:9]1[CH2:10]C2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:31]C(N1C(C(=O)NCC(C2C=CC(Br)=CC=2)=O)C2CC1CC2)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][O:31][CH2:12][CH:13]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
Product: CC(C)(C)OC(=O)N1CCOCC1c1ncc(-c2ccc(Br)cc2)[nH]1

Procedure:
Title compound was prepared according to the method employed to prepare 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (Example AS), substituting 3-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-morpholine-4-carboxylic acid tert-butyl ester for 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:53][C:54]1[N:62]=[CH:61][CH:60]=[C:59]([CH3:63])[C:55]=1[C:56](O)=[O:57].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:53][C:54]1[N:62]=[CH:61][CH:60]=[C:59]([CH3:63])[C:55]=1[C:56]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5])=[O:57]
Reactant: COCCOc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Reactant: Cc1ccnc(Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)ccnc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
(R)-[1-(3-Amino-1-methyl-propyl)-piperidin-4-yl]-[4-(2-methoxy-ethoxy)-phenyl]-(4-methyl-pyridin-3-ylmethyl)-amine (0.065 g, 0.15 mmol), EDCI (0.033 g, 0.17 mmol) and HOBT (0.023 g, 0.17 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 2-chloro-4-methyl-nicotinic acid (0.029 g, 0.17 mmol) followed by DIPEA (54 μL, 0.31 mmol) and the resulting mixture was stirred at 25° C. for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (Et2O:MeOH:NH4OH, 88:10:2, v/v/v) afforded 2-chloro-N-((R)-3-{4-[[4-(2-methoxy-ethoxy)-phenyl]-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide (0.068 g, 76%) as a white foam. 1H NMR (CDCl3) δ 0.98 (d, 3H, J=6.0 Hz), 1.06 (m, 1H), 1.25 (m, 1H), 1.58 (m, 2H), 1.82 (m, 3H), 2.11 (br t, 1H), 2.35 (s, 6H), 2.50 (br t, 1H), 2.75-2.89 (m, 3H), 3.21-3.33 (m, 2H), 3.42 (s, 3H), 3.69 (t, 2H, J=4.5 Hz), 3.82 (m, 1H), 3.90 (m, 2H), 4.01 (t, 2H, J=4.5 Hz), 6.59 (d, 2H, J=9.0 Hz), 6.72 (d, 2H, J=9.0 Hz), 6.96 (d, 1H, J=6.0 Hz), 7.03 (d, 1H, J=6.0 Hz), 7.99 (d, 1H, J=6.0 Hz), 8.25 (s, 1H), 8.30 (d, 1H, J=3.0 Hz), 8.38 (br s, 1H). ES-MS m/z 580 (M+H). Anal. Calcd. for C32H42N5O3Cl.0.4 CH2Cl2: C, 63.37; H, 7.02; N, 11.40. Found: C, 63.28; H, 7.16; N, 11.60.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:35]=[CH:34][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]([N:25]([CH3:33])[C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[O:24])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][CH2:61][CH:62]2[CH2:64][O:63]2)=[CH:56][CH:55]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([N:25]([CH3:33])[C:23]([CH2:22][CH2:21][NH:20][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:64][C@H:62]([OH:63])[CH2:61][O:60][C:57]4[CH:58]=[CH:59][C:54]([OH:53])=[CH:55][CH:56]=4)=[CH:35][CH:34]=3)[CH2:17][CH2:16]2)=[O:19])=[O:24])=[CH:31][CH:30]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CN(C(=O)CCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1)c1ccc(Cl)cc1
Solvent: O=CO
Product: CN(C(=O)CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1)c1ccc(Cl)cc1

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(3-[4-chloro(methyl)anilino]-3-oxopropyl)-1-piperidinecarboxamide formate (0.78 g, 1.55 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane according to Procedure G to provide the title compound (0.27 g, 0.3 mmol)
Reaction SMILES: II.CO.[OH-].[Na+].SCCO.[C:11]([OH:42])(=[O:41])[CH2:12][CH2:13][C@H:14]([NH:18][C:19]([C:21]1[CH:40]=[CH:39][C:24]([NH:25][CH2:26][CH:27]2[NH:38][C:37]3[C:35](=[O:36])[NH:34][C:32]([NH2:33])=[N:31][C:30]=3[NH:29][CH2:28]2)=[CH:23][CH:22]=1)=[O:20])[C:15]([OH:17])=[O:16].C(O)(=O)CC[C@H](NC(C1C=CC(NCC2CNC3N=C(NC(C=3N=2)=O)N)=CC=1)=O)C(O)=O.C1C(C(NC(C([O-])=O)CCC([O-])=O)=O)=CC=C(N)C=1.C1N(C2C=CC(C(=O)N[C@H](C(O)=O)CCC(O)=O)=CC=2)CC2N1C1C(=O)NC(N)=NC=1NC2>Cl>[C:11]([OH:42])(=[O:41])[CH2:12][CH2:13][C@H:14]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][C:24]([NH:25][CH2:26][C@@H:27]2[NH:38][C:37]3[C:35](=[O:36])[NH:34][C:32]([NH2:33])=[N:31][C:30]=3[NH:29][CH2:28]2)=[CH:39][CH:40]=1)=[O:20])[C:15]([OH:17])=[O:16]
Reactant: Nc1nc2c(c(=O)[nH]1)NC(CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Agent: Cl
Agent: II
Agent: Nc1ccc(C(=O)NC(CCC(=O)[O-])C(=O)[O-])cc1
Solvent: CO
Product: Nc1nc2c(c(=O)[nH]1)N[C@@H](CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Temperature: 27 °C
Reaction time: 0.03 h

Procedure:
A solution of crude XVIb (1.34 mmol) in 30 mL 0.01M HCl was cooled to 18° C., and 33 mL of 50 mM I2 in MeOH (1.65 mmol) was added over 10 s with good stirring, with a consequent increase in temperature to 27° C. After 2.0 min, the mixture was cooled within 2.7 min to -20° C. This temperature was maintained during subsequent titration to pH 9.2 (measured without dilution) with 10M NaOH over a period of 1.5 min. The reaction was rapidly warmed to 0° C., and at the same time sparged vigorously with argon. After 3.0 min at 0° C., 58 mL of 0.1M Na2S2O4 (freshly dissolved in deaerated water) was added all at once with stirring, followed 2.0 min later by 0.82 mL 2-mercaptoethanol (11.7 mmol). Analysis by cation exchange HPLC indicated 0.74 mmol of tetrahydrofolic acid (55%). Contaminating impurities included small amounts of 7,8-dihydrofolic acid (XXIIIb), XIXb (λmax =290 nm, pH 3.0), PABA-glu, and trace N5,N10-methylene-tetrahydrofolic acid, with 74% of the 285 nm absorbance area located in the peak of desired product.