Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:15]1[N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17](=[O:25])[C:18]2[CH:24]=[N:23][CH:22]=[CH:21][C:19]=2[N:20]=1)[CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1>Br.C(O)(=O)C>[NH2:10][CH:11]([C:15]1[N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17](=[O:25])[C:18]2[CH:24]=[N:23][CH:22]=[CH:21][C:19]=2[N:20]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)C(NC(=O)OCc1ccccc1)c1nc2ccncc2c(=O)n1Cc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)C(N)c1nc2ccncc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Formula 107a where R1, R3 and R4 are H; R5 is Benzyl; R6 is Isopropyl; R6′ is H; W, Y and Z are —C═; and X is —N═: [1-(3-Benzyl-4-oxo-3,4-dihydro-pyrido[4,3-d]pyrimidin-2-yl)-2-methyl-propyl]-carbamic acid benzyl ester (0.850 g, 1.92 mmol) was dissolved in a solution of HBr/acetic acid (16 mL, 30% wt) and the mixture stirred for 2 hours at room temperature. The solvents were removed under reduced pressure to give the corresponding de-protected amine of Formula 107a, 2-(1-amino-2-methyl-propyl)-3-benzyl-3H-pyrido[4,3-d]pyrimidin-4-one, as a solid HBr salt, which was taken on without further purification. MS (Cl) M/E: 309.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[K+].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Br)c1
Reactant: CCCCCCCBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCOc1ccc(C(=O)O)cc1Br
Temperature: 25 °C

Procedure:
25.8 g (0.119 mol) of the 3-bromo-4-hydroxybenzoic acid prepared in Step I was dissolved in 615 ml ethanol and 42.6 g (0.238 mol) of heptyl bromide was added to the solution. Aqueous potassium hydroxide (13.5 g of potassium hydroxide in 62 ml of water) was added with heating and the above solution was refluxed for ten hours. 125 ml of 10% aqueous potassium hydroxide was added and the solution was refluxed for two more hours. The reaction solution was allowed to stand to cool to room temperature, and excess 5 N hydrochloric acid solution was added commencing crystallization. The crystals were fractionated through filtration by suction, washed with water, dried and recrystallized with ethanol to yield 32.2 of purified 3-bromo-4-n-heptyloxybenzoic acid. The yield was calculated to be 85.9%.
Reaction SMILES: CC(C)([O-])C.[K+].C(OP([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(OCC)=O)C.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:26]([CH:29]=1)[CH:27]=O.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:30][CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:26]([CH:29]=1)[CH:27]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cc(Cl)ccc1OCCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cc(Cl)ccc1OCCc1ccccc1
Reaction time: 1 h
Yield: 168.7 %

Procedure:
In an argon gas stream, 3.49 g of potassium t-butoxide was added to a solution of 8.36 g of ethyl diethylphosphonoacetate in 100 ml of tetrahydrofuran under ice-cooling. The obtained mixture was then stirred at the same temperature for 1 hour. Next, a solution of 5.40 g of 5-chloro-2-(2-phenylethoxy)benzaldehyde in 30 ml of tetrahydrofuran was added dropwise to the reaction mixture and the resulting mixture was stirred at the same temperature for 1 hour and then at room temperature for 19 hours. After adding 30 ml of a saturated aqueous solution of sodium hydrogencarbonate, the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, 11.56 g of crude ethyl 5-chloro-2-(2-phenylethoxy)cinnamate was obtained. Thus compound was not purified any more but used in the subsequent reaction as such.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)C.C(NC1C=C(S(NC2C3C=NN(CC(O)=O)C=3CCC=2)(=O)=O)C=CC=1)(=O)C1C=CC=CC=1>>[C:26]([NH:25][C:21]1[CH:20]=[C:19]([S:16]([NH:15][CH:10]2[CH2:11][CH2:12][CH2:13][C:14]3[N:6]([CH2:5][C:4]([OH:34])=[O:3])[N:7]=[CH:8][C:9]2=3)(=[O:17])=[O:18])[CH:24]=[CH:23][CH:22]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(NC(=O)c2ccccc2)c1
Agent: O=C(O)Cn1ncc2c1CCC=C2NS(=O)(=O)c1cccc(NC(=O)c2ccccc2)c1
Product: O=C(O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(NC(=O)c2ccccc2)c1

Procedure:
Starting with [4-(3-benzoylamino-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester using the method analogous to the one described for example 1-1a, [4-(3-benzoylamino-benzenesulfonylamino)-6,7-dihydro-indazol-1-yl]-acetic acid (11.0 mg, 50%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 8.48 (s, 1H), 7.98 (m, 3H), 7.73-7.52 (m, 5H), 6.79 (s, 1H), 4.78 (s, 2H), 4.42 (s, 1H), 2.55 (m, 2H), 2.04-1.77 (m, 4H). MS cald. for C22H22N4O5S 454, obsd. (ESI+) [(M+H)+] 455.
Reaction SMILES: O[CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH3:10]>>[NH2:10][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: N
Reactant: CCOC(=O)CC(C)O
Product: CCOC(=O)CC(C)N
Reaction time: 0 h

Procedure:
The concentrations of the substrates prior to entering the reactor were 0.226 M for ethyl 3-hydroxy-n-butyrate and 1.630 M for aqueous ammonia. The reaction time was 0.201 second, and the aqueous solution obtained after the reaction was examined with a high performance liquid chromatography/mass spectroscopy apparatus, which confirmed that an amino group had been introduced into the ethyl 3-hydroxy-n-butyrate, and that ethyl 3-amino-n-butyrate had been produced. The ethyl 3-amino-n-butyrate concentration was 3.3 mM, and the reaction yield thereof was 1.5%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25](O)=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1>O1CCCC1>[N:44]1[CH:45]=[CH:46][CH:47]=[C:42]([NH:41][C:25](=[O:26])[C@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:43]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: Nc1cccnc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)Nc1cccnc1
Reaction time: 0.25 h
Yield: 22.6 %

Procedure:
N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine (I) (3.71 g) was dissolved in dry tetrahydrofuran (100 ml) and, under ice cooling, triethylamine (1.5 ml) was added thereto. After stirring for 15 minutes, ethyl chlorocarbonate (1.10 g) was added, followed by stirring for 30 minutes. To this solution was added 3-aminopyridine (0.94 g) and the reaction was carried out at room temperature for 7 hours. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate. After a conventional post-treatment, N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine 3-pyridylamide (II) (1.01 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:11]1([Mg]Br)[CH2:13][CH2:12]1.C1(C(C2C=CC(Cl)=CC=2)O)CC1>O1CCCC1>[CH:11]1([CH:4]([C:3]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=2[Cl:1])[OH:5])[CH2:13][CH2:12]1
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: Br[Mg]C1CC1
Agent: OC(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1Cl)C1CC1

Procedure:
The title compound was prepared starting from 1.50 g (9.46 mmol) of 2-chloro-4-fluorobenzaldehyde and 28.4 ml (14.19 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from Example 153A. 1.51 g (80% of theory) of the title compound were obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13]O)=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>C(Cl)(Cl)Cl.C(OC(C)C)(C)C>[CH2:1]([N:8]1[C:12]([CH2:13][Cl:29])=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1c(-c2ccccc2)c(-c2ccccc2)nn1Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC(C)OC(C)C
Product: ClCc1c(-c2ccccc2)c(-c2ccccc2)nn1Cc1ccccc1
Temperature: -5 °C

Procedure:
60 grams of 1-benzyl-3,4-diphenyl-5-hydroxymethylpyrazole dissolved in 150 ml of anhydrous chloroform are added to 51 ml of thionyl chloride dissolved in 450 ml of anhydrous chloroform, which has been cooled to -5° C. The solution is heated for 3 hours under reflux whilst being stirred. It is then cooled to ambient temperature and the chloroform is evapoated under reduced pressure. The residue is dissolved in 200 ml of petroleum ether and then suspended in 100 ml of diisopropyl ether. 53.4 grams of 1-benzyl-3,4-diphenyl-5-chloromethylpyrazole melting at 99° C are thus obtained.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]([CH3:30])[CH2:27][CH2:28][OH:29])=[N:24][CH:25]=1>>[OH:29][CH2:28][CH2:27][N:26]([CH3:30])[C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CN(CCO)c1ccc(N)cn1
Product: CN(CCO)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 43 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 2-[(5-amino-pyridin-2-yl)-methyl-amino]-ethanol. LCMS calcd for C19H17F3N4O3 (m/e) 406, obsd 407 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C@@H:5]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH2:6][NH:7][C:8](=[O:30])[CH2:9][CH2:10][NH:11][C:12](=[O:29])[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[NH:28])[NH:20]C(OC(C)(C)C)=O)=[CH:15][CH:14]=1)[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:41])[C@@H:5]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:33])=[O:34])[CH2:6][NH:7][C:8](=[O:30])[CH2:9][CH2:10][NH:11][C:12](=[O:29])[C:13]1[CH:14]=[CH:15][C:16]([C:19](=[NH:20])[NH2:28])=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](CNC(=O)CCNC(=O)c1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)NS(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](CNC(=O)CCNC(=O)c1ccc(C(=N)N)cc1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
(2S)-2-Benzenesulfonylamino-3-(3-(4-(N-t-butoxycarbonylamidino)benzoylamino)propanoylamino)propanoic acid ethyl ester (1.48 g) obtained in the same manner as in the synthesis of the compound of Example 1-(8) is dissolved in TFA (50 ml) under ice-cooling, and the mixture is stirred at room temperature for one hour. The reaction mixture is concentrated under reduced pressure, and the residue is washed with ether, and purified by HPLC to give the title compound (448 mg) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3]#[C:4][CH:5]=[CH:6][CH2:7][NH:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[CH3:1][C:2]([CH3:11])([CH3:10])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[Br:18])[CH3:9]
Reactant: BrCc1ccccc1Br
Reactant: CNCC=CC#CC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C/C=C/C#CC(C)(C)C)Cc1ccccc1Br
Yield: 56.4 %

Procedure:
The procedure described in Example 1 was repeated, except that N-(6,6-dimethyl-2-hepten-4-ynyl)methylamine (1.96 g; 13.0 mmol), potassium carbonate (1.44 g; 13.6 mmol), and 2-bromobenzylbromide (3.25 g; 13.0 mmol) were used, to thereby yield 2.35 g of the target compound (yield: 56.5%).
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19]OCC)[C:14](OCC)=[O:15])[CH3:10].O.Cl>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[C:14]([OH:15])=[N:7][C:6]([NH2:8])=[N:5][CH:19]=1)=[O:23])[CH3:10]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)N
Agent: Cl
Agent: O=C(O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc(N)nc1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 83.3 %

Procedure:
Guanidine carbonate (18.0 g, 200 mmol) is dissolved in ethanol (300 ml), and then sodium alcoholate (13.6 g) and ethoxymethylenemalonic acid diethyl ester (43.2 g, 200 mmol) are added at room temperature. After stirring at room temperature for 4 days, the mixture is concentrated to dryness under reduced pressure. To the residue obtained, water (500 ml) is added and neutralized with hydrochloric acid, and then the crystal precipitated is collected by filtration and recrystallized, to yield a white crystal (30.5 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([CH3:22])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=2)[C:16]2[CH:21]=[C:20]([CH3:22])[S:19][C:17]=2[N:18]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: Cc1cc2c(Cl)nc(Cl)nc2s1
Product: COc1ccc(CNc2nc(Cl)nc3sc(C)cc23)cc1Cl

Procedure:
Following the procedure of Example 1, the reaction of 3-chloro-4-methoxybenzylamine with 2,4-dichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].Br[CH:37]([CH2:39][CH3:40])[CH3:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH:37]([CH2:39][CH3:40])[CH3:38])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: CCC(C)Br
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: CCC(C)Oc1ccc(OC)c2c1CCN(CC(=O)NCc1ccccn1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with 2-bromo-butane
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[CH2:5][CH2:4][CH2:3][C:2]2=[O:8].[Li+].CC([N-]C(C)C)C.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19]>C1COCC1>[CH:1]12[CH2:7][CH:6]1[CH2:5][CH2:4][CH:3]=[C:2]2[O:8][Si:18]([CH3:20])([CH3:19])[CH3:17]
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCCC2CC12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OC1=CCCC2CC12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Add dropwise bicyclo[4.1.0]heptan-2-one (43.3 g, 0.393 mol) in dry THF (50 mL) to a solution of LDA (237 mL, 0.472 mol) in THF (500 mL). Stir the reaction mixture for 30 min and then add dropwise TMSCl (64.2 g, 0.59 mol) to the reaction mixture. Stir the resultant solution for additional 1 hour. Pour the mixture into ice water (92 mL) and extract the aqueous mixture with EtOAc (100 mL×3). The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford crude (bicyclo[4.1.0]hept-2-en-2-yloxy)-trimethyl-silane (68.0 g, 95.0%) as yellowish oil, MS (m/z): 181 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:26]([O-])=O)=[CH:4][C:5]([CH3:25])=[C:6]([CH:24]=1)[O:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C([O-])=O.[NH4+].C1(C)C=CC=CC=1>[Fe].O>[NH2:26][C:3]1[C:2]([Cl:1])=[CH:24][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH2:12]2)=[C:5]([CH3:25])[CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(N)c(Cl)cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Yield: 88.9 %

Procedure:
A flask was charged with tert-butyl 4-(3-(5-chloro-2-methyl-4-nitrophenoxy)propyl)-piperazine-1-carboxylate (1.2 g, 2.9 mmol), ammonium formate (0.84 g, 13 mmol), and iron powder (0.74 g, 13 mmol). Toluene (20 mL) and water (20 mL) were added to the flask and the mixture was heated to reflux for 6 hours, after which time, the mixture was filtered through a plug of Celite. The supernatant was extracted with ethyl acetate and water. The organic solvent was removed on a rotary evaporator under reduced pressure to yield tert-butyl 4-(3-(4-amino-5-chloro-2-methylphenoxy)propyl)piperazine-1-carboxylate as a brown oil (0.99 g, 89% yield). 1H-NMR (400 MHz, DMSO-d6): δ 6.77 (s, 1H), 6.61 (s, 1H), 4.76 (s, 2H), 3.86 (t, 6.1 Hz, 2H), 3.30 (s, br, 4H), 2.50 (m, 2H), 2.31 (m, 2H), 2.03 (s, 3H), 1.82 (m, 2H), 1.39 (s, 9H). MS (EI): 384 (MH+).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[C@@H:15]2[C:16](=[O:18])[CH2:17][C@@:11]1([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:12]([O:19][CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[C@@H:15]2[C@@H:16]([OH:18])[CH2:17][C@@:11]1([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:12]([O:19][CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:22]=1)[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O[C@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
Sodium borohydride (55 mg, 1.44 mmol) was added to a stirred solution of (1R*,2R*,5S*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-one (Example 41; 50 mg 0.09 mmol) in methanol (3 ml) at +5° C. The reaction mixture was stirred for 15 minutes and quenched with saturated aqueous NaHCO3 and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 10-45%) to give the title, compound (35 mg, 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:16]([O:15][C:13]([N:12]1[C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[NH:1][C:28]1=[O:30])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)n2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 171.1 %

Procedure:
Part 2. To a chilled solution of methyl 3-amino-4-[(tert-butoxy)carbonylamino]benzoate (0.40 g, 1.5 mmol) in CH2Cl2 (10 mL) and triethylamine (0.21 mL, 1.5 mmol) was added a solution of triphosgene (161 mg, 0.54 mmol) in CH2Cl2 (6 mL) over 5 min. The reaction was stirred at room temperature for 2 hr, diluted with CH2Cl2, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography using 50% ethyl acetate in CH2Cl2 as eluent to give methyl 1-[(tert-butyl)oxycarbonyl]-2-oxo-(3H)—benzimidazole-5-carboxylate (0.27 g, 61%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6](O)[CH2:5][C:4]1=[O:58])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]=[CH:5][C:4]1=[O:58])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)C=CC1=O)C(C)CC2OC

Procedure:
A solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-azido-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (210 mg, Example 2, step 2E) and a catalytic amount of p-toluenesulfonic acid in 40 ml of dry benzene was refluxed for 2.5 h under nitrogen atmosphere. The solvent was removed under reduced pressure and the dark brown residue was purified by column chromatography on silica gel (40% ethyl acetate/hexane) to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.[Cl:28]C1C=C(C)C=CN=1>>[Cl:28][C:2]1[CH:3]=[C:4]([CH2:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:15]=2)=[O:9])[CH:5]=[CH:6][N:1]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: O=C(Cc1ccnc(Cl)c1)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone but substituting 2-chloro-4-methyl pyridine provided the title compound. MS: (M+H m/z=389.0).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][O:9][CH2:10][CH:11]2[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13][CH2:12]2)[C:5]([NH:19][CH:20]=O)=[CH:4][N:3]=1>C(OC(OC(=O)C)OCC)C>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([N:19]=[CH:20][N:8]2[O:9][CH2:10][CH:11]2[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13][CH2:12]2)=[CH:4][N:3]=1
Reactant: CC1(C)OCC(CONc2nc(Cl)ncc2NC=O)CO1
Agent: CCOC(OCC)OC(C)=O
Product: CC1(C)OCC(COn2cnc3cnc(Cl)nc32)CO1
Temperature: 20 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
2-Chloro-4-(2,2-dimethyl-1,3-dioxan-5-ylmethoxyamino)-5-formamidopyrimidine (3.45 g, 10.9 mmol) in diethoxymethylacetate (100 ml) was heated at 120° C. for 2 hours. The mixture was then cooled and evaporated to a syrup. The residue was dissolved in methanol (50 ml) and concentrated aqueous ammonia (2.5 ml). The solution was then stirred at 20° C. for 1 hour, evaporated under reduced pressure and the residue co-evaporated with toluene. Column chromatography on silica gel (eluted with chloroform-methanol, 60:1) gave the title compound (2.27 g, 70%). IR: υmax (KBr) 3117, 2993, 1599, 1571, 1339 cm-1. 1H NMR: δH [(CD3)2SO] 1.33 (3H,s,CH3), 1.37 (3H,s,CH3), 2.08 (1H,m,CH), 3.81 (2H,d.d, J=5.8, 2.1 Hz, 2×H(ax)). 4.04 (2H, d.d, J=4.0, 12.0 Hz. 2×H (eq)), 4.52 (2H, d, J=3.3 Hz, CH2ON), 9.00 (1H,s,H-8), 9.14(1H,s,H-6). Found: C, 48.34; H, 5.13; N, 18.66%: C12H15ClN4O3 requires: C, 48.24; H, 5.07; N, 18.76%.