Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.[CH:25]([C:27]1([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1)=O.C(C1(C(OC)=O)CCC1)=O>>[O:22]1[CH2:23][CH2:24][CH:19]([O:18][C:14]2[C:13]3[C:9]([O:8][CH2:7][CH:4]4[CH2:3][CH2:2][N:1]([CH2:25][C:27]5([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:6][CH2:5]4)=[N:10][O:11][C:12]=3[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21]1
Reactant: c1cc(OC2CCOCC2)c2c(OCC3CCNCC3)noc2c1
Reactant: COC(=O)C1(C=O)CCCC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(OC5CCOCC5)c34)CC2)CCCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 3-(piperidin-4-ylmethoxy)-4-(tetrahydro-2H-pyran-4-yloxy)-1,2-benzisoxazole (EXAMPLE 27, Step 1) and methyl 1-formylcyclopentanecarboxylate (Synthesis, 1997, 32) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:17][O:18][C:19](=[O:29])[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1[NH2:28].CCCCCC>CCOC(C)=O>[CH3:17][O:18][C:19](=[O:29])[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=1[NH:28][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH3:12]
Reactant: COC(=O)c1c(N)cc(Cl)cc1Cl
Reactant: CC(C(=O)O)c1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(Br)cc1
Yield: 47 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-(4-bromo-phenyl)-propionic acid (11.7 g, 48.3 mmol), SOCl2 (35.0 mL, 480 mmol), and 2-amino-4,6-dichloro-benzoic acid methyl ester (10.1 g, 45.9 mmol). After normal workup, the pure objective compound (9.31 g, 55%) was obtained as white solid by a flash column chromatography (n-hexane:EtOAc=10:1): 1H NMR (200 MHz, CDCl3) δ 1.58 (d, J=7.1 Hz, 3H, CH3), 3.75 (q, J=7.1 Hz, 1H, CH), 3.81 (s, 3H, CO2CH3), 7.15 (d, J=2.0 Hz, 1H, ArH), 7.20-7.53 (m, 4H, ArH), 8.41 (d, J=1.7 Hz, 1H, ArH), 9.16 (br s, 1H, NH).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](=[O:15])[CH2:11][N:12]([CH3:14])[CH3:13].[CH3:20][Mg]I.[Mg].CI>CCOCC>[CH3:13][N:12]([CH3:14])[CH2:11][C:10]([C:6]1[N:5]([CH2:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=2[F:1])[CH:9]=[CH:8][CH:7]=1)([OH:15])[CH3:20]
Reactant: C[Mg]I
Reactant: CN(C)CC(=O)c1cccn1Cc1ccccc1F
Agent: [Mg]
Solvent: CCOCC
Solvent: CI
Product: CN(C)CC(C)(O)c1cccn1Cc1ccccc1F

Procedure:
A solution of 16.0 g of 1-(o-fluorobenzyl)-2-(dimethylaminoacetyl)pyrrole, free base of Example 3a, in 60 ml of ether is treated with a solution of methylmagnesium iodide, prepared from 2.7 g of magnesium turnings and 15.3 g of methyl iodide, in 40 ml of ether according to the procedure described in Example 9a to produce a crude yellow oil of 1-(dimethylamino)-2-[1-(o-fluorobenzyl)-2-pyrryl]-2-hydroxypropane. Distillation at 130°-138° C/0.1 mm affords the product as a faintly yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.C(OC([N:15]1[C:19]2[C:20]([CH3:24])([CH3:23])[NH:21][CH2:22][C:18]=2[C:17]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)=[N:16]1)=O)C.[F:36][C:37]1([C:44](Cl)=[O:45])[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1>C(Cl)Cl>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[C:26]([NH:25][C:17]1[C:18]2[CH2:22][N:21]([C:44]([C:37]3([F:36])[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[O:45])[C:20]([CH3:24])([CH3:23])[C:19]=2[NH:15][N:16]=1)=[O:35]
Reactant: CN1CCC(F)(C(=O)Cl)CC1
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(Cl)c(Cl)c2)c2c1C(C)(C)NC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(F)(C(=O)N2Cc3c(NC(=O)c4ccc(Cl)c(Cl)c4)n[nH]c3C2(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DIEA (0.220 mL, 1.66 mmol) and 3-(3,4-Dichloro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylic acid ethyl ester (221 mg, 0.51 mmol) were added to a solution of 4-Fluoro-1-methyl-piperidine-4-carbonyl chloride (0.51 mmol) in CH2Cl2 (10 mL). The reaction was stirred at RT for 4 h. The mixture was quenched with H2O (30 mL), extracted with CHCl3 (2×30 mL). The organic layers were dried over MgSO4 and concentrated to give the title compound as brown color oil which was used without further purification. ESI (MNa+): 564.10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:26]=[CH:25][C:16]([O:17][CH:18]([CH3:24])[C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2.[OH-].[K+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:24])[C:19]([OH:21])=[O:20])=[CH:25][CH:26]=1)[CH:6]=[CH:5]2
Reactant: CCOC(=O)C(C)Oc1ccc(Oc2ccc3cc(Cl)ccc3n2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(Oc1ccc(Oc2ccc3cc(Cl)ccc3n2)cc1)C(=O)O
Reaction time: 24 h

Procedure:
A solution of ethyl 2-[4-(6-chloro-2-quinolinyloxy)phenoxy]propionate (2.0 g) and potassium hydroxide (1.0 g) in methanol (20 ml) was warmed and stirred for 24 hours. The solution was poured into dilute hydrochloric acid (100 ml, 0.5 m) and extracted with ethyl acetate (2×50 ml). The ethyl acetate extracts were dried (MgSO4) and evaporated to give 2-[4-(6-chloro-2-quinolinyloxy)phenoxy]propionic acid as a brown solid, mp 130° C. Mass spectrum (m/e): 343 (patent ion, 80%); 270 (80%); 164 (70%); 162 (100%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Cl:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[C:23]([CH3:28])[N:22]=1.N12CCCN=C1CCCCC2>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:20][C:21]1[N:26]=[C:25]([N:17]2[CH2:18][CH2:19][CH:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=4)[CH2:9][CH2:10]3)[CH2:15][CH2:16]2)[CH:24]=[C:23]([CH3:28])[N:22]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: Cc1cnc(N2CCC(C3CCNCC3)CC2)cn1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: Cc1cnc(N2CCC(C3CCN(c4cc(C)nc(Cl)n4)CC3)CC2)cn1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
The 1-(5-methylpyrazin-2-yl)-4,4′-bipiperidine (720 mg, 2.8 mmol) and 2,4-dichloro-6-methyl-pyrimidine (502 mg, 3.1 mmol) were dissolved in NMP (30 mL), and the solution cooled to −20° C. The 1,8-diazabicyclo[5.4.0]-undec-7-ene (4.2 mL, 28 mmol) was added drop-wise and the solution stirred for 10 minutes. The mixture was diluted with ethyl acetate (50 mL), washed with brine (30 mL×2), dried over magnesium sulfate, filtered and concentrated in vac. The residue was purified by chromatography on silica gel with 30% acetone: hexanes to yield the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>C(OCC)(=O)C>[CH2:12]([NH:16][C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCNC(=O)CCc1ccccc1

Procedure:
Following the procedure of Example 1 above and using 3-phenylpropionyl chloride and n-butylamine (and ethyl acetate in place of benzene), the title compound was prepared as a white solid, m.p. 26.7-33.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH:21]=O)=[CH:13][CH:12]=2)[CH:3]=1.CN.[C:25]([BH3-])#[N:26].[Na+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)(=O)C.CO>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][NH:26][CH3:25])=[CH:13][CH:12]=2)[CH:3]=1
Reactant: [BH3-]C#N
Reactant: N#Cc1ccc(Cl)cc1Oc1ccc(C=O)c2ccccc12
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1ccc(Oc2cc(Cl)ccc2C#N)c2ccccc12
Yield: 74.7 %

Procedure:
4-Chloro-2-(4-formylnaphthalen-1-yloxy)benzonitrile (0.34 g, 1.1 mmol), methylamine (2M in methanol, 2.0 mL, 4.0 mmol) and sodium cyanoborohydride (80 mg, 1.3 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (30 mL) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.12 g, 1.0 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-[4-(methylaminomethyl)naphthalen-1-yloxy]benzonitrile fumarate (328 mg, 68%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[NH2:18][C:19](=[N:31]O)[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=1[F:30]>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:10][N:31]=[C:19]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=3[F:30])[N:18]=2)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Reactant: COC(=O)c1ccc(C(N)=NO)c(F)c1
Product: COC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(C)c3)n2)c(F)c1

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 3 (113.1 mg; 0.50 mmol; 1 eq.) and Intermediate 2 (106.1 mg; 0.50 mmol; 1 eq.). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound as a off-white solid. LC/MS (Method A): 403.0 (M+H)+. HPLC (Method A) Rt 6.20 min (Purity: 96.8%).
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]([OH:13])=[O:12])=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:16][CH2:15]1.[CH:30]1(N2C3N=CN=C(N4CCC(N5C6C=CC=CC=6NC5=O)CC4)C=3N=C(OC)C2=O)C[CH2:31]1.[OH-].[Na+]>CO>[CH:1]1([N:2]2[C:10]([C:11]([OH:13])=[O:12])=[N:9][C:8]3[C:3]2=[N:4][CH:5]=[N:6][C:7]=3[N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[NH:22][C:21]3=[O:29])[CH2:16][CH2:15]2)[CH2:31][CH2:30]1
Reactant: Cn1c(C(=O)O)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Reactant: COc1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n(C2CC2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C1CC1

Procedure:
9-Cyclopropyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxylic acid was prepared in the same manner as 9-methyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxylic acid. The 8-cyclopropyl-6-methoxy-4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]pteridin-7(8H)-one (0.836 g, 1.93 mmol) was treated with 2M sodium hydroxide (10 mL, 20 mmol) in methanol at 80° C. for 18 hours gave 0.789 of 9-cyclopropyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxylic acid as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.20 (br s, 1H), 8.07 (s, 1H), 6.93 (m, 1H), 6.71 (m, 3H), 5.19 (broad s, 2H), 4.27 (m, 1H), 3.40 (m, 2H), 3.19 (t, 2H), 2.43 (m, 2H), 1.82 (d, 2H), 1.15 (m, 2H), 0.84 (m, 2H). MS (EI) for C21H21N7O4: 420 (MH+).
Reaction SMILES: O1CCCC1.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[C:18]1[NH:23][C:22](=[O:24])[C:21]2=[C:25]([CH3:33])[N:26]=[C:27]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:20]2[N:19]=1)[CH3:7]>C(O)C.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:6][CH3:7])=[C:10]([C:18]2[NH:23][C:22](=[O:24])[C:21]3=[C:25]([CH3:33])[N:26]=[C:27]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[N:20]3[N:19]=2)[CH:11]=1
Reactant: CCOc1ccc([N+](=O)[O-])cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
In 86 ml of ethanol and 86 ml of tetrahydrofuran 2.56 g (6.68 mmol) of the compound from example 41A are stirred in the presence of 288 mg of Pd/C (10%) under an H2 atmosphere for 20 hours. The reaction solution is filtered with suction through 30 ml of silica gel, the filter cake is washed with ethanol/tetrahydrofuran and the filtrate is concentrated and dried under high vacuum overnight. The crude product is chromatographed on 500 ml of silica gel using toluene and ethyl acetate in a gradient system.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([N:16]2[CH2:8][CH2:7][CH:2]2[C:3]([O:5][CH3:6])=[O:4])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)C(Br)CCBr
Reactant: NC1CCCCC1
Product: COC(=O)C1CCN1C1CCCCC1
Yield: 76 %

Procedure:
The reaction of methyl 2,4-dibromobutanoate 17 with cyclohexylamine 18A yielded methyl 1-(cyclohexyl)azetidine-2-carboxylate as a brown oil (76%). MS ISP (m/e): 198.2 (100) [(M+H)]+.
Reaction SMILES: [C:1]1([CH:7]([NH2:16])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([O:20]CC)(=[O:19])[CH3:18].C(O)C>>[C:17]([O:20][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:19])[CH3:18].[C:1]1([CH:7]([NH2:16])[CH2:8][C:9]2[CH:10]=[CH:11][C:12]([Br:15])=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(C)=O
Agent: NC(Cc1ccc(Br)cc1)c1ccccc1
Solvent: CCO
Product: CC(=O)Oc1ccccc1
Temperature: 60 °C
Reaction time: 116 h

Procedure:
1-Phenyl-2-(4-bromophenyl)ethylamine (6.71 gm, 2.43×10-2 mol) was dissolved in 40 ml of 25% ethyl acetate/ethanol. This solution was then added to a solution of S(-)-α-methoxy-α-(trifluoromethyl)phenylacetic acid (5.69 gm, 2.43×10-2 mol) in 40 ml of 25% ethyl acetate/ethanol. The resulting solution was warmed to 60° C., and then allowed to stand at room temperature for 116 hours. The mixture was then left in a freezer for 24 hours. The resulting white precipitate was collected by vacuum filtration, washed with ethyl ether, and dried in vacuo to yield the desired (-) -α-methoxy-α-trifluoromethyl)phenyl acetate of (-)-1-phenyl-2-(4-bromophenyl)ethylamine (2.93 gm). The mother liquor was concentrated to dryness under reduced pressure, and the residue was crystallized as described above using 60 ml of 25% ethyl acetate/ethanol to yield an additional 0.63 gm of the phenylacetate of (-)-1-phenyl-2-(4-bromophenyl)ethylamine. The combined precipitates (3.56 gm, 57%, mp=143°-145° C.) were treated with 30 ml of 2.5N aqueous NaOH, extracted with three 30 ml portions of dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to yield the desired (-)-1-phenyl-2-(4-bromophenyl)ethylamine as a yellow oil (1.74 gm, 52%), [α]D25 =-62.7 (EtOH), shown to be 99.8% enantiomerically pure by chiral HPLC.
Reaction SMILES: Cl.C([O:6][C:7](=[O:35])[CH2:8][N:9]([S:17]([C:20]1[CH:29]=[C:28]2[C:23]([C:24]([Cl:34])=[CH:25][N:26]=[C:27]2[NH:30][C:31]([NH2:33])=[NH:32])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(C)(C)C>O1CCOCC1>[ClH:34].[Cl:34][C:24]1[C:23]2[C:28](=[CH:29][C:20]([S:17]([N:9]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:8][C:7]([OH:35])=[O:6])(=[O:18])=[O:19])=[CH:21][CH:22]=2)[C:27]([NH:30][C:31]([NH2:33])=[NH:32])=[N:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)CN(CC1CCCCC1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)CC3CCCCC3)cc12
Temperature: 23 °C
Reaction time: 18 h
Yield: 114 %

Procedure:
A solution of HCl (2 mL, 2 M, 4 mmol) was added to a solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(cyclohexylmethyl)glycine t-butyl ester (53 mg, 0.10 mmol) in dioxane (4.0 mL). The mixture was stirred at 23° C. for 18 h and then heated at 50-60° C. for 16 h. On cooling, a white precipitate crashed out of solution. The solid was collected by filtration, triturated with EtOAc and then dried under vacuum to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(cyclohexylmethyl)glycine hydrochloride (26 mg, 0.057 mmol).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:12]1([N:30]([CH3:32])[CH3:31])[CH2:17][CH2:16][CH:15]([C:18]2[NH:19][C:20]3[C:25]([C:26]=2[CH3:27])=[CH:24][C:23]([O:28]C)=[CH:22][CH:21]=3)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[CH2:5]([C:12]1([N:30]([CH3:32])[CH3:31])[CH2:13][CH2:14][CH:15]([C:18]2[NH:19][C:20]3[C:25]([C:26]=2[CH3:27])=[CH:24][C:23]([OH:28])=[CH:22][CH:21]=3)[CH2:16][CH2:17]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc2[nH]c(C3CCC(Cc4ccccc4)(N(C)C)CC3)c(C)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(C2CCC(Cc3ccccc3)(N(C)C)CC2)[nH]c2ccc(O)cc12

Procedure:
A 1 M solution of BBr3 in methylene chloride (1.03 ml, 1.03 mmol) was added to a solution of 1-benzyl-4-(5-methoxy-3-methyl-1H-indol-2-yl)-N,N-dimethylcyclohexanamine (more polar diastereoisomer, 130 mg, 0.345 mmol) in dry methylene chloride (20 ml) at RT, while stirring and with exclusion of moisture. After 10 min a precipitate precipitated out. The mixture was stirred at RT for 24 h.—For working up, sat. NaHCO3 solution (15 ml) was added to the mixture and the mixture was stirred for 48 h. The organic phase was separated off and the aqueous phase was extracted with methylene chloride (3×10 ml). The combined organic phases were dried over Na2SO4 and then concentrated. 2-(4-Benzyl-4-(dimethylamino)cyclohexyl)-3-methyl-1H-indol-5-ol (polar diastereomer) was obtained in this way in a yield of 63 mg (50%).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:12]=2)=[CH:8][CH:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[OH:3][CH2:4][C:6]1[O:10][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:12]=2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(-c2nn(CCc3ccccc3)c3ccccc23)o1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc(-c2nn(CCc3ccccc3)c3ccccc23)o1
Reaction time: 1 h

Procedure:
A solution of 300 mg (0.83 mmol) of 3-(5-ethoxycarbonyl-2-furyl)-1-(2-phenylethyl)indazole in 10 ml of THF was added dropwise to 31.5 mg (0.83 mmol) of lithium aluminum hydride in 10 ml of THF. After 1 h, the mixture was admixed with 25% strength potassium carbonate solution and the precipitate was separated off and washed with THF. The combined THF filtrates were dried and concentrated. The crude product was purified by silica gel chromatography using dichloromethane/methanol (95:5). This gave 200 mg (75%) of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[CH:11]=[CH:10][C:9]=1[O:20]COC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[CH:11]=[CH:10][C:9]=1[OH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc(N2CCCC2=O)cc1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCCN1c1ccc(O)c(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
A mixture of 505 mg of 2-benzyl-1-methoxymethyloxy-4-(2-pyrrolidinon-1-yl)benzene and 5 ml of trifluoroacetic acid was stirred at room temperature for 1 hour. The reaction mixture was evaporated, and the residue was purified by silica gel column chromatography with 30–60% ethyl acetate/hexane, to give 320 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[CH3:54][O:55][C:56](C1C=CC(C(O)=O)=CC=1)=[O:57].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:28][O:27][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[N:14]=[N:15][C:10]([CH:8]([NH:7][C:5]([C:4]3[CH:29]=[CH:30][C:31]([C:56]([O:55][CH3:54])=[O:57])=[CH:2][CH:3]=3)=[O:6])[CH3:9])=[CH:11][N:12]=2)[CH:22]=[C:21]([O:23][CH3:24])[C:20]=1[O:25][CH3:26]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NC(C)c2cnc(Nc3cc(OC)c(OC)c(OC)c3)nn2)cc1
Yield: 100 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (87 mg, 0.28 mmol), 4-(methoxycarbonyl)benzoic acid (67 mg, 0.37 mmol), diisopropylethylamine (0.13 mL, 0.75 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (140 mg, 0.37 mmol) in dimethylformamide (2 mL) gave methyl 4-{[(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)amino]carbonyl}benzoate (131 mg, 100%) as a yellow oil. MS m/z 467 (M+1).
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]([C@@H:9]1[CH2:14][CH2:13][C@@H:12]([NH2:15])[C@H:11]([OH:16])[CH2:10]1)=[O:8].[C:17](=O)([O:23]C(C)(C)C)[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:5][O:6][C:7]([C@@H:9]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:17]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:23])[C@H:11]([OH:16])[CH2:10]1)=[O:8]
Reactant: COC(=O)[C@@H]1CC[C@@H](N)[C@H](O)C1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)C1
Temperature: 50 °C
Yield: 102.6 %

Procedure:
The acetate salt (c) (15.6 g, 66 mmol) was suspended in tetrahydrofuran (200 ml) and treated with di-tert-butyl carbonate (16 g, 73 mmol) and diisopropylethylamine (14 ml, 10.4 g, 80 mmol). The mixture was heated at 50° C. for 18 hours then evaporated to dryness. The residue was partitioned between water and ethyl acetate. The aqueous phase was further extracted with ethyl acetate and the combined extracts washed with brine, dried and evaporated to give a solid (18.5 g, 100%).
Reaction SMILES: [C:1]1([C:7]2([C:10](=[S:12])[NH2:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15]([C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)=O>CCO>[C:1]1([C:7]2([C:10]3[S:12][C:15]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)=[CH:14][N:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: NC(=S)C1(c2ccccc2)CC1
Solvent: CCO
Product: N#Cc1ccc(-c2cnc(C3(c4ccccc4)CC3)s2)cc1

Procedure:
1-Phenylcyclopropanecarbothioamide (1-2, 0.050 g, 0.282 mmol) and 4-(bromoacetyl)benzonitrile (1-3, 0.063 g, 0.282 mmol) were combined in a dry flask, and dissolved in EtOH (10.0 mL). The resulting solution was refluxed for 2 h, and the product precipitated from the reaction upon cooling. The solid was filtered, washed with EtOH (3×5 mL) and dried under vacuum to provide 4-[2-(1-phenylcyclopropyl)-1,3-thiazol-5-yl]benzonitrile (1-4) as a tan solid: 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J=8.2 Hz, 2H), 7.68 (d, J=8.2 Hz, 2H), 7.51 (d, J=7.6 Hz, 2H), 7.39 (m, 4H), 1.86 (dd, J=6.8, 3.9 Hz, 2H), 1.48 (dd, J=6.8, 3.9 Hz, 2H); MS 303.0 found 305.2 (M+H+) required.