Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.Cl.[NH:20]([CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[NH2:21].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:20]([CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:21]=1
Reactant: NNCc1ccncc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1ccccc1-c1nc(-c2ccccc2O)n(Cc2ccncc2)n1

Procedure:
5.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one are boiled under reflux for 4 h with 5.9 g of 4-hydrazinomethylpyridine hydrochloride in [CAS-Reg. No.: 89598-56-1] and 10 ml of triethylamine in 50 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, 3,5-bis(2-hydroxyphenyl)-1-(pyridin-4-ylmethyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 197-199° C.
Reaction SMILES: C[O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12]1)[CH2:10][C:9]2=[O:29].[OH-].[Na+]>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:13]2[CH2:14][CH2:15][CH2:16][C:11]3([CH2:10][C:9](=[O:29])[C:8]4[C:26](=[CH:27][CH:28]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:30])=[O:2])[CH:7]=4)[O:25]3)[CH2:12]2)=[CH:19][CH:20]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccc(F)cc3)C1)O2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccc(F)cc3)C1)O2
Yield: 84.7 %

Procedure:
(±)-(E)-3-[1′-(4-Fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (630 mg, 1.54 mmol) was treated with 1 M NaOH according to the procedure described in Example 16 STEP B to give (±)-(E)-3-[1′-(4-fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid (516 mg, 85%).
Reaction SMILES: [I-:1].[Na+].[C:3]([O:7][C:8]([NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18]OS(C)(=O)=O)[CH2:14][CH2:13]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CC(C)=O>[C:3]([O:7][C:8]([NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][I:1])[CH2:14][CH2:13]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CI)CC1

Procedure:
In 130 ml of anhydrous acetone was dissolved 13.24.g of trans-N-t-butoxycarbonyl-4-methanesulfonyloxymethylcyclohexylmethylamine, and 12.32 g of sodium iodide was added thereto, and the resulting mixture was heated under reflux for 3 hours and 45 minutes. The solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The resulting solution was washed successively with an aqueous sodium thiosulfate solution and an aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluting solvent: cyclohexane/ethyl acetate=4/1) to obtain a pale yellow crystalline solid. The crystalline solid was recrystallized from hexane to obtain 13.67 g of the desired compound as a colorless crystalline solid.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C@@H:10]2[CH2:15][C@H:14]([C:16]3[O:20][NH:19][C:18](=[O:21])[CH:17]=3)[CH2:13][CH2:12][N:11]2C(OC)=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br>>[C:1]([C:5]1[S:9][C:8]([C@@H:10]2[CH2:15][C@H:14]([C:16]3[O:20][NH:19][C:18](=[O:21])[CH:17]=3)[CH2:13][CH2:12][NH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1c1ccc(C(C)(C)C)s1
Agent: Br
Product: CC(C)(C)c1ccc([C@@H]2C[C@H](c3cc(=O)[nH]o3)CCN2)s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 16.3 %

Procedure:
(2S,4R)-Methyl 2-(5-tert-butylthiophen-2-yl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (50 mg, 0.14 mmol) (from example 42, step 3) was dissolved in hydrobromic acid (33% in AcOH, 1 mL, 6.08 mmol) and stirred at room temperature for 20 h. The solvent was evaporated in vacuo. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×19 ID mm) using a gradient of 10-50% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 25 minutes with a flow of 19 mL/min. 5-((2S,4R)-2-(5-tert-Butylthiophen-2-yl)piperidin-4-yl)isoxazol-3(2H)-one (7.00 mg, 16.65%) was isolated as a white solid. 1H NMR (600 MHz, cd3od) δ 1.36 (s, 9H), 2.03-2.12 (m, 1H), 2.12-2.19 (m, 1H), 2.26-2.33 (m, 1H), 2.40-2.46 (m, 1H), 3.09-3.17 (m, 1H), 3.18-3.24 (m, 1H), 3.34-3.40 (m, 1H), 4.38-4.44 (m, 1H), 5.75 (s, 1H), 6.78 (d, 1H), 6.96 (d, 1H).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]([F:34])([F:33])[C:17]1[C:27]2[S:26][C:25]3[CH:28]=[CH:29][CH2:30][CH2:31][C:24]=3[NH:23][C:22](=O)[C:21]=2[CH:20]=[CH:19][CH:18]=1.O>N1C=CC=CC=1>[F:15][C:16]([F:34])([F:33])[C:17]1[C:27]2[S:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[NH:23][C:22](=[S:2])[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: O=C1NC2=C(C=CCC2)Sc2c1cccc2C(F)(F)F
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: c1ccncc1
Product: FC(F)(F)c1cccc2c1Sc1ccccc1NC2=S
Yield: 80.8 %

Procedure:
Phosphorus pentasulphide (0.6 g, 2.5 mmol) was added to a stirred solution of 4-trifluoromethyl-9,10-dihydrodibenzo[b,f][1,4]thiazepin-11-one (0.59 g, 2 mmol) in pyridine (20 ml). The mixture was heated under reflux for 6.5 hr and then at room temperature overnight before hot water (40 ml) added. Filtration and recrystallisation from ethanol gave the title compound as fine yellow needles (0.503 g, m.p. 265°-267° C., Rf 0.65, petrol/EtOAc 1:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1>C(CN)O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12]([NH:13][CH2:14][CH2:15][OH:21])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Solvent: NCCO
Product: Cc1ccccc1-n1ccc2c(NCCO)nc3c(OCC(F)(F)F)cccc3c21
Temperature: 180 °C
Yield: 152.1 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-β,β,β-trifluoroethoxypyrrolo[3,2-c]quinoline(391 mg, 1.0 mmol), prepared by the procedures of Step 1 and Step 2 in the Example 34, was dissolved in ethanolamine(10 ml) in the pressure tube, and the resultant was refluxed at 180° C. for 3 hours. After removing the excess ethanolamine by distillation under reduced pressure, the residue was diluted in dichloromethane(20 ml), and washed with water(15 ml) for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 316 mg of desired compound as solid in 75% of yield.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[NH2:6].[CH3:18][S:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[NH:6][C:29]([C:24]1([CH2:23][CH2:22][CH2:21][CH2:20][S:19][CH3:18])[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:30]
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: CSCCCCC1(C(=O)O)CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)C1(CCCCSC)CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.1 %

Procedure:
To a suspension of 4-nitro-L-phenylalanine methyl ester hydrochloride salt (181.84 mmol, 47.41 g), 1-[4-(methylthio)butyl]cyclopentanecarboxylic acid (177.17 mmol, 38.33 g) in DMF (470 mL) were added HBTU (177.17 mmol, 67.2 g) and diisopropylethylamine (443 mmol, 77 mL) at room temperature. The clear solution was stirred for 15 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting materials. The reaction mixture was diluted with 600 mL of ethyl acetate then was washed in turn with 0.5N hydrochloric acid (2×250 mL), saturated sodium bicarbonate solution (2×250 mL) and brine (300 mL). The dried (MgSO4) organic layer was filtered and evaporated to dryness under reduced pressure. The crude product which was purified by silica gel column chromatography to afford 58.5 g (78%) of N-[[1-[4-(methylthio)butyl]cyclopentyl]carbonyl]-4-nitro-L-phenylalanine methyl ester as an amorphous colorless solid. HRMS: Obs. mass, 423.1940. Calcd. mass, 423.1953 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[N:15]2[CH3:18])=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:10]=1.C1N=CN([C:41](N2C=NC=C2)=[O:42])C=1>C(#N)C>[OH:29][C:26]([CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][C:14]2[N:15]([CH3:18])[C:16]3[C:12]([N:13]=2)=[C:11]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[N:10]=[C:9]([N:8]2[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[NH:1][C:41]2=[O:42])[N:17]=3)[CH2:25][CH2:24]1)([CH3:28])[CH3:27]
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(=O)[nH]c4ccccc43)nc21
Yield: 15.9 %

Procedure:
A mixture of 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (40 mg, 0.083 mmol) and N,N-carbonyldiimidazole (17 mg, 0.108 mmol) in acetonitrile (2 mL) was stirred at reflux for 15 hours. The reaction mixture was then filtered through paper and purified by RP-HPLC to give 156 (6.7 mg, 16%). LCMS: M+H+=507.2. 1H-NMR (400 MHz, DMSO-d6): δ 11.0 (s, 1H), 7.55 (d, 1H), 7.04 (m, 3H), 4.21 (s, br, 4H), 4.02 (s, 1H), 3.78 (s, 3H), 3.74 (m, 6H), 2.88 (m, 2H), 2.00 (m, 2H), 1.66 (m, 2H), 1.20 (m, 3H), 1.02 (s, 6H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[H][H]>[Ni].CO>[C:27]([O:26][C:24]([NH:23][CH:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:31])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1)[C:20]([OH:22])=[O:21])=[O:25])([CH3:29])([CH3:30])[CH3:28]
Reactant: COC(=O)C=Cc1ccc(-c2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COC(=O)CCc1ccc(-c2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Yield: 92.2 %

Procedure:
Raney nickel 2800 (4.0 g) was added to a degassed solution of the unsaturated ester 43 (4.1 g) in MeOH (150 mL) and the resulting suspension was treated with hydrogen at atmospheric pressure for 18 h. The suspension was filtered over a Celite® bed and concentrated. Flash chromatography (30-50% ethyl acetate in hexane containing 1% acetic acid) of the resulting residue gave the desired saturated ester 44 (3.8 g, 94.5%). 1H NMR (400 MHz, DMSO-d6): 7.54 (d, J=7.6 Hz, 4H), 7.31 (overlapped d, J=8.8 Hz, 2H), 7.29 (overlapped d, J=8.4 Hz, 2H), 4.12 (m, 1H), 3.58 (s, 3H), 2.87 (t, J=7.6 Hz, 2H), 2.65 (t, J 7.6 Hz, 2H), 1.31 (s, 9H).
Reaction SMILES: C[S-].[Na+].[Br:4][C:5]1[C:13]([O:14]C)=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[O:16]>CN(C)C=O>[Br:4][C:5]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[O:16]
Reactant: COc1ccc2c(c1Br)CCC2=O
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2c1ccc(O)c2Br
Temperature: 130 °C
Reaction time: 2 h

Procedure:
Sodium methanethiolate (2.00 g) is added to a microwave vial charged with a stir bar, 4-bromo-5-methoxy-indan-1-one (1.58 g), and N,N-dimethylformamide (10 mL). The vial is sealed and the mixture is heated to 130° C. and stirred at this temperature for 2 h. After cooling to room temperature, the mixture is partitioned between ethyl acetate and 1 N aqueous HCl solution. The aqueous phase is separated and extracted with ethyl acetate. The combined organic phases are washed with brine and dried (MgSO4). The solvents are evaporated and the residue is triturated with diethylether. The precipitate is filtered off and dried in vacuo to give the title compound. LC (method 1): tR=0.84 min; Mass spectrum (ESI+): m/z=227/229 (Br) [M+H]+.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([CH:46]=O)=[CH:40]2>C1COCC1>[Cl:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([CH:46]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:40]2
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc2cc(Cl)ccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC=Cc1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
To the cold suspension of pentyl triphenyl-phosphonium bromide in THF was added LiHMDS in THF and the mixture was stirred for 30 minutes and then the solution of 5-chloro-1H-indole-2-carbaldehyde was added to the reaction mixture and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The product, 5-chloro-2-hex-1-enyl-1H-indole was purified by column chromatography.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][N:14]=2)[C:10]#[N:11])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH3:19][C:20]([CH3:22])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[CH:20]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][N:14]=2)[C:10]#[N:11])[CH2:6][CH2:5]1)([CH3:22])[CH3:19]
Reactant: N#Cc1ccnc(N2CCNCC2)c1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CCN(c2cc(C#N)ccn2)CC1
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a solution of 2-piperazin-1-yl-isonicotinonitrile (10 g, 53 mmol), glacial acetic acid (4.26 ml, 4.5 g, 74.4 mmol, 1.4 equiv) and acetone (4.29 ml, 3.39 g, 58 mmol, 1.1 equiv) in anhydrous dichloromethane was added sodium triacetoxyborohydride (13.5 g, 63.8 mmol, 1.2 equiv). The reaction was stirred overnight, then an aqueous solution of 1N NaOH solution was added (150 ml) and the mixture was extracted once with dichloromethane, then twice with a solution of 10% methanol/dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography (5% methanol/CH2Cl2 grading to 10% methanol/CH2Cl2) provided the desired product (6.52 g, 59%). MS m/z 231 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=4)[CH:17]3[C:27]([O:29][CH3:30])=[O:28])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N:33]1([CH2:38][CH2:39]O)[CH:37]=[CH:36][N:35]=[CH:34]1.FC1C=CC(OC2C=CC(S(N3CCC4C(=CC=C(OCCCN5CCN(C)CC5)C=4)C3C(OC)=O)(=O)=O)=CC=2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([S:13]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:39][CH2:38][N:33]5[CH:37]=[CH:36][N:35]=[CH:34]5)[CH:22]=4)[CH:17]3[C:27]([O:29][CH3:30])=[O:28])(=[O:14])=[O:15])=[CH:11][CH:12]=2)=[CH:31][CH:32]=1
Reactant: COC(=O)C1c2ccc(O)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: OCCn1ccnc1
Agent: COC(=O)C1c2ccc(OCCCN3CCN(C)CC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Product: COC(=O)C1c2ccc(OCCn3ccnc3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Methyl 2-[4-(4-fluorophenoxy)benzenesulfonyl]-6-hydroxy-1,2,3,4-tetrahydro-isoquinoline-1-carboxylate (3B) is reacted with 2-imidazol-1-ylethanol by the method described under 3C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6]1)=[O:4].C(NC(C)C)(C)C.[Li].Cl[C:22]([O:24][CH3:25])=[O:23]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:8]1)=[O:4]
Reactant: CCCCC1CC(C(=O)OC)C1
Reactant: COC(=O)Cl
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCC1CC(C(=O)OC)(C(=O)OC)C1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A solution of 3-butyl-cyclobutanecarboxylic acid methyl ester (7.75 g, 45.6 mmol) in THF (30 mL) was added dropwise to a solution of lithium diisopropylamine (7.26 g, 68.4 mmol) in THF (70 mL) at −78° C. After stirring for 1.5 h at the same temperature, methyl chloroformate (6.46 g, 68.4 mmol) was added slowly and the mixture was allowed to warm to room temperature. After 18 h the reaction mixture was quenched with saturated aqueous NH4Cl solution (200 mL) and the aqueous residue was extracted with EtOAc (75 mL×5). The combined organic layers were dried (MgSO4). After removal of the solvent under reduced pressure, purification by flash column chromatography using an eluting system of hexane/EtOAc (95:5) yielded the title compound as a clear yellow oil (8.37 g, 81%). MH+229.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C@@H:9]([CH3:10])[C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][C:6]1=[O:17].[CH3:22][O:23][C:24](=[O:43])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=1>>[CH3:22][O:23][C:24](=[O:43])[CH2:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=2[CH2:4][N:5]2[C@@H:9]([CH3:10])[C@@H:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:17])[C:29]([O:32][CH3:33])=[CH:30][CH:31]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1ccccc1Br
Reactant: COC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccccc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (4S,5R)-3-(2-bromo-benzyl)-4-methyl-5-phenyl-oxazolidin-2-one and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38]CC1C=CC=CC=1)=[O:37]>[Pd].C(OCC)(=O)C.CO>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:10][CH2:11]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37]
Reactant: O=C(CCCCCN1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)CCCCCN1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
To a solution of benzyl 6-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)hexanoate (0.25 g, 0.41 mmol) in 4:1 ratio of ethyl acetate/methanol (4 mL), was added 10 wt % palladium on carbon (0.1 g). After stirring under hydrogen at room temperature and atmospheric pressure for 2 hours, the reaction mixture was filtered, washed with 1% acetic acid in methanol, concentrated in vacuo and isolated by reverse phase HPLC to obtain the title compound (0.09 g, 42%); 1H NMR (DMSO-d6): δ 1.21-1.26 (m, 2H), 1.47-1.57 (m, 6H), 1.77-1.82 (m, 2H), 2.18 (t, 2H, J=7.2 Hz), 2.32 (t, 2H, J=6.4 Hz), 2.59-2.67 (m, 6H), 2.91 (d, 2H, J=11.2 Hz), 3.84 (t, 2H, J=6.4 Hz), 4.64 (s, 2H), 6.76 (t, 1H, J=7.2 Hz), 6.88 (d, 2H, J=8.4 Hz), 6.96 (d, 3H, J=3.6 Hz), 7.18-7.20 (m, 1H), 7.24 (t, 2H, J=8.8 Hz), 10.82 (s, 1H); MS for C29H37N5O4 m/z 520.08 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH:13]=[C:12]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Reactant: Oc1ccc(Cl)cc1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Oc3ccc(Cl)cc3)c2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-chloro-phenol and (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-chloro-phenoxy)-7-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 381(MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15].[Cl:18][C:19]1[S:23][C:22]([CH:24]=O)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH:16][CH2:24][C:22]1[S:23][C:19]([Cl:18])=[CH:20][CH:21]=1)[CH3:15]
Reactant: O=Cc1ccc(Cl)s1
Reactant: CC(C)(N)COc1ccc2ccccc2c1Cl
Product: CC(C)(COc1ccc2ccccc2c1Cl)NCc1ccc(Cl)s1
Yield: 29 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-amine and 5-chlorothiophen-2 carbaldehyde in 29% yield as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][C@H:15]([CH3:19])[NH:14]1.C[C@H]1CN(CC2C=CC([N+]([O-])=O)=CC=2)CCN1C(OC(C)(C)C)=O>>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:17]2[CH2:16][C@H:15]([CH3:19])[NH:14][C@H:13]([CH3:12])[CH2:18]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C
Product: C[C@@H]1CN(Cc2ccc([N+](=O)[O-])cc2)C[C@H](C)N1

Procedure:
The title compound was prepared from 4-nitrobenzaldehyde and (2R,6S)-2,6-dimethylpiperazine using a method similar to that described for D1 in Description 1A. MS (ES): MH+ 250.2
Reaction SMILES: [N:1]1([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]C)=[O:21])=[CH:15][C:14]=2[O:24][CH3:25])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[N:1]1([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:14]=2[O:24][CH3:25])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)Cc1ccc(NC(=O)N2CCc3ccccc32)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(CC(=O)O)ccc1NC(=O)N1CCc2ccccc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
A mixture of methyl 4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl-acetate (5.2 g, Reference Example 6) and sodium hydroxide (20 mL, 1M) in methanol (100 mL) and water (50 mL) was stirred at 50° C. for 4 hours. The mixture was evaporated to low bulk and the aqueous layer was washed with dichloromethane then acidified with hydrochloric acid (1M) to give a tan precipitate. This material was filtered, washed with water, then with ether and then dried to give the title compound (4.3 g) as an off-white solid. HPLC: RT=13.3 minutes (99% by ELS).