Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[I:7]I.[NH2:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:12](=[O:23])[N:11]=1.OS(O)(=O)=O.[O-]S([O-])=O.[Na+].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[NH2:9][C:10]1[C:15]([I:7])=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:12](=[O:23])[N:11]=1
Reactant: II
Reactant: Nc1ccn(-c2ccc(F)cc2)c(=O)n1
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(=O)n(-c2ccc(F)cc2)cc1I
Temperature: 80 °C
Reaction time: 4 h
Yield: 209.1 %

Procedure:
Sodium metaperiodate (0.21 g, 0.97 mmol) and iodine (0.495 g, 1.95 mmol) were added to a stirred solution of 4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one (1 g, 4.87 mmol) in a mixture of acetic acid (12 mL), water (3 mL) and H2SO4 (0.4 mL). The mixture was stirred at 80° C. for 4 hours. The mixture was poured onto an ice-cold 10% aqueous solution of Na2SO3 and then neutralized with a 2N aqueous solution of NaOH to pH 7. A solid was formed, filtered and washed with water and EtOH to yield 4-amino-1-(4-fluoro-phenyl)-5-iodo-1H-pyrimidin-2-one (1.35 g, 84% yield) as a white solid, that was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2O.P(Cl)(Cl)([Cl:15])=O.C(N(CC)CC)C.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2ccc(Cl)cc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1ccc2ncnc(Cl)c2c1

Procedure:
Preparation D1, Step 2: 6-Chloroquinazolin-4-ol (400 mg, 2.21 mmol, 1 eq.), phosphorus oxychloride (1.99 mL, 21.4 mmol, 9.64 eq.) and triethylamine (0.99 mL, 7.11 mmol, 3.21 eq.) were mixed at room temperature under nitrogen and then refluxed for 2.5 hours. Worked up by stripping the reaction, then re-rotovapping the residue 2 times from toluene to obtain brown solids. Methylene chloride (25 mL) was added to dissolve the solids. The organic mixture was then rinsed 2 times with saturated ammonium chloride (25 mL). The organic layer was dried (sodium sulfate) and stripped to give brown solids. The solids were purified over silica gel in 9:1 to 3:1 hexanes/ethyl acetate. Obtained 4,6-dichloroquinazoline (300 mg) as an off-white solid. Yield=68%. 1H NMR (400 MHz) (DMSO-D6) δ 9.16 (s, 1H): 8.33 (s, 1H), 8.17 (apparent t, 2H, J=7 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:25](=[CH:26][CH:27]=1)[CH2:24][C:8]1[C:9]3[CH:15]=[CH:14][C:13]([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:12][C:10]=3[O:11][C:7]=1[C:6]2([CH3:29])[CH3:28].Cl([O-])=[O:31].[Na+].ON1C(=O)C2=CC=CC=C2C1=O.C(Cl)Cl>C(#N)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:31])[C:8]1[C:9]3[CH:15]=[CH:14][C:13]([O:16][S:17]([C:20]([F:21])([F:23])[F:22])(=[O:18])=[O:19])=[CH:12][C:10]=3[O:11][C:7]=1[C:6]2([CH3:29])[CH3:28]
Reactant: COc1ccc2c(c1)C(C)(C)c1oc3cc(OS(=O)(=O)C(F)(F)F)ccc3c1C2
Reactant: [O-][Cl+][O-]
Agent: O=C1c2ccccc2C(=O)N1O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)c1oc3cc(OS(=O)(=O)C(F)(F)F)ccc3c1C2=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
Trifluoromethanesulfonic acid 8-methoxy-6,6-dimethyl-6,11-dihydro-benzo[b]naphth[2,3-d]furan-3-yl ester (Compound Z11, 4.82 g) was dissolved in acetonitrile (48 mL) and water (24 mL), added with sodium chlorite (2.55 g) and N-hydroxyphthalimide (369 mg), and then the mixture was stirred at 40° C. for 1 hr. The reaction mixture was added with methylene chloride and the organic layer was washed with saturated brine. Thereafter, the organic layer was dried over magnesium sulfate. The residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (2.80 g, 56%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13]Br.CN(C)C=O.O.[N-:22]=[N+:23]=[N-:24].[Na+]>C(OC)(C)(C)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13][N:22]=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1CN=[N+]=[N-]
Reaction time: 8 h
Yield: 89.6 %

Procedure:
10 g (36.5 mmol) of 2-(bromomethyl)-3-nitrobenzoic acid methyl ester is mixed with 36 ml of N,N-dimethylformamide and 24 ml of water. After 3.54 g of sodium azide is added, the batch is stirred overnight. The reaction mixture is diluted with methyl tert-butyl ether, and washed twice with water and once with brine. After drying on sodium sulfate, it is filtered, and the solvent is spun off. The desired azide is obtained in a yield of 89.6% (7.72 g) and further incorporated in crude form.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](C3SC=CC=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:18][CH2:19][O:20]S(C1C=CC(C)=CC=1)(=O)=O.C([O:33][C:34](=[O:55])[C:35]([O:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:47])[CH2:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1)C>C(O)C>[C:11]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:10]=[CH:9][CH:8]=[C:7]([C:5]2[O:6][C:2]([CH3:1])=[C:3]([CH2:18][CH2:19][O:20][C:40]3[C:41]4[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:37]([CH2:36][C:35]([CH3:47])([O:48][C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:34]([OH:33])=[O:55])=[CH:38][CH:39]=3)[N:4]=2)[CH:12]=1
Reactant: CCOC(=O)C(C)(Cc1cccc2ccccc12)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)c2ccccc12
Temperature: 55 °C
Yield: 7 %

Procedure:
Toluene-4-sulfonic acid 2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)-ethyl ester (0.132 mmol) (see Ex. 3, Part B) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 2-phenoxy-3-(naphthalen-1-yl)-2-methylpropionic acid ethyl ester (see Ex. 12, Part B) (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100·1) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of hew hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150·1), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by mass-directed HPLC to produce a white solid (7%). MS [EI+] 590 (M+H)+, [EI−] 588 (M−H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[Li+].CC([N-]C(C)C)C.[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]1([CH2:26][C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[CH3:29])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:6][CH2:5]1
Reactant: Cc1ccccc1CBr
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccccc2C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of N-t-butoxycarbonyl isonipecotic acid methyl ester (10.1 g 41.8 mmol) in 140 ml of dry THF at −78° C. was added LDA (59 ml of a 1.0 M solution in THF, 59 mmol) over 15 min. The resulting orange solution was stirred at −78° C. for 1 hr and then treated dropwise with 2-methylbenzyl bromide (6.80 ml, 50.7 mmol) and then allowed to warm slowly to room temperature over 16 hrs. The reaction was quenched with saturated aqueous NH4Cl, diluted with H2O, and extracted with EtOAc. The combined organic extracts were washed with brine, and concentrated in vacuo to an orange gum. Chromatography (SiO2, eluting with 20 to 30% EtOAc in hexanes) and evaporation of solvent in vacuo, afforded the product as a white solid.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C:12](Cl)=[O:13].[NH2:20][C:21]1[N:25]([C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][C:27]=2[Cl:37])[N:24]=[CH:23][CH:22]=1>ClCCl>[Cl:7][C:8]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C:12]([NH:20][C:21]1[N:25]([C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33]([F:34])([F:36])[F:35])=[CH:28][C:27]=2[Cl:37])[N:24]=[CH:23][CH:22]=1)=[O:13]
Reactant: Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
2.2 ml (0.0275 mol) of anhydrous pyridine and 6.7 g (0.027 mol) of 96.3 percent strength 2,4-dichlorophenoxyacetyl chloride are added successively to 8 g (0.027 mol) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (cf. U.S. Pat. No. 4,614,533, supra, in 60 ml of dichloromethane with stirring at 0° C. to 5° C. and the mixture is stirred for 16 hours at room temperature. The mixture is worked up by adding 100 ml of dichloromethane, washing successively with dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, drying the organic phase over magnesium sulphate and removing the solvent in vacuo. 12.7 g (94.3% of theory) of 5-(2,4-dichlorophenoxyacetamido)-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole of melting point 167° C.-180° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:22]1[CH:23]=[N:24][CH:25]=[N:26][CH:27]=1.[O:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.CCOC(C)=O.[Cu](I)I>[O:33]=[C:29]1[N:30]([C:2]2[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)=[O:7])=[CH:4][C:3]=2[C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)[CH2:31][CH2:32][O:28]1
Reactant: O=C1NCCO1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(Br)c(-c2cncnc2)c1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CCOC2=O)c(-c2cncnc2)c1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
4-Bromo-3-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 117.1, 100 mg, 0.228 mmol), oxazolidin-2-one (79 mg, 0.913 mmol), copper iodide (4.35 mg, 0.023 mmol) and finely ground K3PO4 (143 mg, 0.672 mmol) were added to a MW vial. The vial was sealed, evacuated/purged with argon and a solution of trans-N,N′-dimethylcyclohexane-1,2-diamine (7.20 μL, 0.046 mmol) in dioxane (456 μL) was added. The RM was then stirred at 110° C. for 20 hr. The RM was diluted with EtOAc (5 mL), washed with 1M HCl (20 mL) and extracted with EtOAc. The combined extracts were sequentially washed with NH4OH (32%)/NH4Cl (sat.) 1:5 (10 mL), and brine (10 mL), dried over Na2SO4, and the mixture was evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1), from 20% to 90% EtOAc-EtOH+0.1% NH4OH (9:1)). Second purification was performed by preparative HPLC (Condition 13, from 5% to 100% in 14 min) afforded the title compound as a brown solid. UPLC-MS (condition 1) tR=2.13 min, m/z=445.1 [M+H]+, m/z=443.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 4.03-4.21 (m, 2H) 4.32-4.49 (m, 2H) 7.39 (d, J=8.31 Hz, 2H) 7.72-7.83 (m, 1H) 7.84-7.93 (m, 2H) 8.06-8.17 (m, 2H) 8.96 (s, 2H) 9.22 (s, 1H) 10.49 (s, 1H).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[N:12](OC(C)(C)C)=[O:13].Cl>O1CCCC1>[C:6]1([C:1](=[O:5])[C:2](=[N:12][OH:13])[CH2:3][CH3:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCC(=O)c1ccccc1
Reactant: CC(C)(C)ON=O
Agent: Cl
Solvent: C1CCOC1
Product: CCC(=NO)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a stirred solution of the butyrophenone (300 mg, 2.0 mmol) in tetrahydrofuran (8 mL) was added t-butyl nitrite (0.475 mL, 4.0 mmol) and hydrochloric acid (4N in dioxane, 0.65 mL, 2.6 mmol). The reaction was stirred at RT for 3 hours, then the solvent was evaporated and the residue was purified by Prep HPLC (ammonium acetate/water/acetonitrile) to give the title material (0.200 g, 56%). HPLC 91% (220 nm), LCMS (+ESI, M+H+) m/z 178; 1H NMR (400 MHz, methanol-d4) δ (ppm): 1.13 (3H, t, J=7.6 Hz), 2.71 (2H, qa, J=7.6 Hz), 7.45 (2H, br t), 7.57 (1H, br t), 7.90 (2H, d, J=7.0 Hz).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[S:3]1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:14]1([C:11]([C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2](=[O:1])[S:3][C:4]=3[CH:10]=2)=[O:13])[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]c(=O)sc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]c(=O)sc2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 74 %

Procedure:
The title compound is prepared from 2-oxo-2,3-dihydro-benzothiazole-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 74% of theory; LC (method 3): tR=2.28 min; Mass spectrum (ESI+): m/z=351 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([CH:6]([C:11]2[CH:12]=[C:13]([N:18]3[CH:22]=[N:21][N:20]=[CH:19]3)[CH:14]=[C:15]([F:17])[CH:16]=2)[C:7]([F:10])([CH3:9])[CH3:8])[CH2:3]1.Br[CH:24]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29].C(N(C(C)C)CC)(C)C>CC#N>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([CH:24]([N:2]2[CH2:3][CH:4]([CH:6]([C:11]3[CH:12]=[C:13]([N:18]4[CH:19]=[N:20][N:21]=[CH:22]4)[CH:14]=[C:15]([F:17])[CH:16]=3)[C:7]([F:10])([CH3:9])[CH3:8])[CH2:5]2)[C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])=[CH:38][CH:37]=1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Reactant: CC(C)(F)C(c1cc(F)cc(-n2cnnc2)c1)C1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(F)C(c1cc(F)cc(-n2cnnc2)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1

Procedure:
A sample of 135 mg (0.41 mmole) of 4-[3-(1-Azetidin-3-yl-2-fluoro-2-methylpropyl)-5-fluorophenyl]-4H-1,2,4-triazole hydrochloride, 211 mg (0.62 mmole) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile and 181 uL (1.025 mmole) of diisopropylethylamine in 5 mL of dry CH3CN was heated at reflux for 3 h. The solution was concentrated and the residue was dissolved in 20 mL of CH2Cl2 and 5 mL of NaHCO3. The layers were separated and the organic phase was dried over Na2SO4 and concentrated. The residue was purified on silica gel using CH2Cl2-EtOAc—NH3 (2M in MeOH), 200:50:4 to afford the title compound as a mixture of 4 diastereomers: Mass Spectrum: m/e=518 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:2]1.[NH:17]1[C:25]2[C:20](=[C:21]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[NH:17]1[C:25]2[C:20](=[C:21]([N:26]3[CH2:31][CH2:30][N:29]([C@@H:13]4[CH2:14][CH2:15][C@H:10]([C:3]5[C:4]6[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=6)[NH:1][CH:2]=5)[CH2:11][CH2:12]4)[CH2:28][CH2:27]3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1
Reactant: O=C1CCC(c2c[nH]c3ccccc23)CC1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: c1cc(N2CCN([C@H]3CC[C@@H](c4c[nH]c5ccccc54)CC3)CC2)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(1H-indol-3-yl)-cyclohexanone (0.53 g, 2.5 mmol), 1-(indol-4-yl)piperazine (0.5 g, 2.5 mmol), sodium triacetoxyborohydride (0.78 g, 3.5 mmol) and acetic acid (0.14 ml, 2.5 mmol) in 1,2-dichloroethane (11 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3×60 ml), and washed with brine (3×60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 0.52 g (53%) of product as a white solid: mp 85-87° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@@H:14]([NH2:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>ClCCl.CCOCC>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:17][C@@H:14]2[C@@H:12]3[C@@H:11]([CH2:10][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[N:8]=4)[CH2:13]3)[CH2:16][CH2:15]2)=[O:29])=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 264 Step A (0.050 g, 0.184 mmol) in dichloromethane (0.1 mL) was added 1-fluoro-4-isocyanatobenzene (0.025 mL, 0.221 mmol). The reaction was stirred at ambient temperature for 30 minutes. The reaction was diluted with ether and sonicated, then filtered and washed with ether to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.45 (s, 1H), 7.63 (dd, J=9.1, 4.9, 2H), 7.46 (t, J=7.9, 1H), 7.00 (t, J=8.8, 2H), 6.93 (d, J=8.8, 1H), 6.51 (d, J=7.7, 1H), 6.21 (d, J=6.7, 1H), 4.27-4.12 (m, 1H), 3.73-3.44 (m, 3H), 3.28 (dd, J=11.0, 4.0, 1H), 2.77-2.57 (m, 2H), 2.12 (td, J=12.7, 6.8, 1H), 1.87 (td, J=13.3, 7.9, 1H), 1.57 (dq, J=12.8, 7.8, 1H), 1.37 (dtd, J=13.2, 7.8, 5.3, 1H); MS (ESI+) m/z 409 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18]=3[O:27][CH3:28])=[O:16])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[BH4-].[Na+].[Cl-].[NH4+]>O.C(Cl)(Cl)Cl>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18]=3[O:27][CH3:28])[OH:16])[CH2:10][CH2:9]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1ccc(C(=O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)c(OC)c1OC
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1ccc(C(O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)c(OC)c1OC
Yield: 69.9 %

Procedure:
13.8 g (30 mmol) of 2-(4-diphenylmethylpiperazinyl)-1-(2,3,4-trimethoxyphenyl)ethanone was dissolved in a mixed solvent consisting of 100 ml of ethanol and 30 ml of chloroform, followed by addition of 2.27 g (60 mmol) of sodium borohydride under ice-cooled conditions over 20 minutes. The resultant mixture was stirred at room temperature for 2 hours, followed by addition of 50 ml of an aqueous saturated solution of ammonium chloride and by further addition of 100 ml of water. The resultant mixture was extracted with 200 ml of ethyl acetate, and the organic layer was successively washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was removed, and the residue was recrystallized from a mixed solvent of chloroform and ethanol to give 9.70 g of 2-(4-diphenylmethylpiperazinyl)-1-(2,3,4-trimethoxyphenyl)ethanol as white crystals (yield: 70%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:36].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C@@H:17]([OH:36])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: [OH-]
Reactant: COc1cc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)cc(OC)c1OC
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc(OC)c1OC

Procedure:
In analogy with Example 44d), 1.097 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(3,4,5-trimethoxyphenyl)methyl]dihydrofuran-2-(3H)-one in 36.48 ml of dimethoxyethane and 18.39 ml of water are hydrolysed with 9.03 ml of 1M lithium hydroxide solution to give the title compound, which is subjected, without purification, to further processing.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH3:16][CH:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:10]1([CH2:9][O:8][C:7]2[N:6]=[C:5]([C:13]([OH:15])=[O:14])[CH:4]=[CH:3][C:2]=2[N:18]2[CH2:19][CH2:20][CH2:21][CH:17]2[CH3:16])[CH2:12][CH2:11]1
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Reactant: CC1CCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC1CCCN1c1ccc(C(=O)O)nc1OCC1CC1
Yield: 36.2 %

Procedure:
Under an atmosphere of nitrogen, a solution of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (Example 9 d, 0.4 g, 1.5 mmol), 2-methylpyrrolidine (CAN 765-38-8, 188 mg, 2.2 mmol), R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (CAN 76189-55-4, 183 mg, 0.3 mmol), tris-(dibenzylidene-acetone)dipalladium (CAN 51364-51-3, 135 mg, 0.15 mmol) and cesium carbonate (1.9 g, 6 mmol) in toluene (50 mL) was heated to 90° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (10 mL) and extracted with ethyl acetate (30 mL), the pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid and the resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 10 g, 50% ethyl acetate in petroleum ether) to yield the title compound (0.15 g, 36.9%) as yellow solid; MS (EI): m/e=277.2 [M+H]+.