Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]([CH:9]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=O.[CH3:11][O:12][CH2:13][C:14]1[CH:15]=[C:16]([NH2:19])[NH:17][N:18]=1>C(O)C>[CH3:11][O:12][CH2:13][C:14]1[CH:15]=[C:16]2[N:19]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:1][N:17]2[N:18]=1
Reactant: CCOC(=O)C(C=O)C=O
Reactant: COCc1cc(N)[nH]n1
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(COC)nn2c1
Reaction time: 8 h
Yield: 69.4 %

Procedure:
Ethyl 2-formyl-3-oxopropionate (775 mg) was added to a solution of the thus obtained 5-methoxymethyl-2H-pyrazol-3-ylamine (684 mg) in ethanol (50 ml), and stirred overnight. The reaction solution was concentrated under reduced pressure, and a saturated sodium bicarbonate solution was added to the residue which were then extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; n-hexane:ethyl acetate 4:1) to give ethyl 2-methoxymethylpyrazolo[1,5-a]pyrimidine-6-carboxylate (878 mg, Y.:69%). 1 M Boron tribromide solution in dichloromethane (0.51 ml) was added dropwise at −70° C. to a solution of the thus obtained ethyl 2-methoxymethylpyrazolo[1,5-a]pyrimidine-6-carboxylate (20 mg) in dichloromethane (2 ml). The temperature of the mixture under stirring was increased from −70° C. to −50° C. over 4.5 hours and then increased from −50° C. to room temperature over 2 hours. The reaction mixture was cooled to 0° C., water was added to the reaction mixture which was then extracted with ethyl acetate, and the extract was dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure to give ethyl 2-hydroxymethylpyrazolo[1,5-a]pyrimidine-6-carboxylate (19 mg, Y.:quant.).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][OH:17].[Na]>O>[C:1]([O:17][CH2:16][CH2:15][N:14]([CH3:18])[CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)CCO
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: CN(C)CCOC(=O)c1ccccc1
Reaction time: 3.25 h
Yield: 61.6 %

Procedure:
A solution of 70.29 grams (0.50 mol) of benzoyl chloride in 500 milliters of methylene chloride was added to a solution of 44.57 grams (0.50 mol) of 2-dimethylaminoethanol, 20.0 grams (0.50 mol) of sodium hydroxideand 500 milliters of water over 15 minutes with rapid stirring. Stirring was continued for 3.25 hours after which the organic layer was separated, washed with water, dried over MgSO4 and concentrated. Distillation of the residue gave 59.5 grams of product; bp=102°-108° C./0.50 min.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:3]=1[CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl-].[NH4+]>C(O)C.[Zn]>[NH2:18][C:15]1[CH:16]=[CH:17][C:2]([Br:1])=[C:3]([CH:14]=1)[CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: CN(Cc1cc([N+](=O)[O-])ccc1Br)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: CN(Cc1cc(N)ccc1Br)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
Zinc (1.042 g, 15.93 mmol) was added to a mixture of tert-butyl 2-bromo-5-nitrobenzyl(methyl)carbamate (1 g, 2.90 mmol) and ammonium chloride (3.10 g, 57.9 mmol) in ethanol (10 mL). The mixture was stirred for 3 h at rt. The mixture was concentrated. Na2CO3 (sat., 50 mL) and EtOAc (50 mL) was added and stirred for 1 h. The phases were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The organics were combined, washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 50% ethyl acetate in hexane over 30 min using a 40 g silica gel cartridge) to yield 12A (0.785 g, 2.490 mmol, 86% yield) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][OH:10])[CH:2]=1.[Cl:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C@@H:19]2[CH3:31])=[N:14][CH:15]=[CH:16][N:17]=1.Cl>>[ClH:11].[CH3:31][C@H:19]1[CH2:20][NH:21][CH2:22][CH2:23][N:18]1[C:13]1[C:12]([O:10][CH2:9][CH2:8][O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:17][CH:16]=[CH:15][N:14]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1Cl
Reactant: OCCOc1cccnc1
Agent: Cl
Product: C[C@H]1CNCCN1c1nccnc1OCCOc1cccnc1
Yield: 58 %

Procedure:
The title compound was prepared starting from 2-(3-pyridyloxy)ethanol (from Example 150, Step 1) and 3-chloro-2-[4-tert-butoxycarbonyl-(2S)-methyl-1-piperazinyl]pyrazine (prepared according to the procedure of Example 172, Step 2, with the exception that (2S)-methylpiperazine was substituted for (2R)-methylpiperazine). MS m/z 316 (M+H)+. Yield 58%; mp 170-172° C. Anal. (C16H21N5O2.1.45 HCl) C, H, N.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:6]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:7]=2[S:8][C:9]=1[C:10]([NH2:12])=[O:11]>CN(C=O)C.C(OCC)(=O)C>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:7]2[S:8][C:9]([C:10]([NH2:12])=[O:11])=[C:5]([S:2][CH3:1])[C:6]=2[CH:16]=1
Reactant: COc1ccc2sc(C(N)=O)c(Cl)c2c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2sc(C(N)=O)c(SC)c2c1
Reaction time: 1 h
Yield: 72 %

Procedure:
Sodium thiomethoxide (93 mg, 1.32 mmol) is added to a suspension of 3-chloro-5-methoxybenzo[b]thiophene-2-carboxamide (250 mg, 1.03 mmol) in 2 mL of DMF. After 1 hour, an additional amount of sodium thiomethoxide (13 mg) is added. The reaction mixture is diluted with ethyl acetate and washed with 1N NaOH, 1N HCl, water, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane gives 5-methoxy-3-(methylthio)benzo[b]thiophene-2-carboxamide in 72% yield; mp=171°-173° C.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[C:10](=[O:15])[CH2:11][CH:12](N)[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Na]>C1(C)C=CC=CC=1.O>[CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[C:10](=[O:15])[CH:11]=[CH:12][CH3:13]
Reactant: C=C1CCCC(C)(C)C1C(=O)CC(C)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C1CCCC(C)(C)C1C(=O)C=CC
Yield: 65.3 %

Procedure:
1 g of 2-methylene-6,6-dimethyl-1-[3-amino-butanoyl]-cyclohexane in 25 ml of toluene was refluxed for 3 hours in the presence of a catalytic amount of p-toluene-sulphonic acid. The obtained solution was wahsed with a 10% solution of sodium hydrogenocarbonate in water until neutrality, then dried and concentrated. 0.6 g of 2-methylene-6,6-dimethyl-1-[but-2-enoyl]-cyclohexane was thus obtained. The analytical data were in agreement with those of a pure sample prepared by one of the known methods.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Cl:5][C:6]1[CH:32]=[CH:31][C:9]([CH2:10][NH:11][C:12]([C:14]2[C:15](=[O:30])[C:16]3[C:17]4[N:18]([CH:29]=2)[CH2:19][C:20](=[O:28])[N:21]([CH3:27])[C:22]=4[CH:23]=[C:24](I)[CH:25]=3)=[O:13])=[CH:8][CH:7]=1>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:5][C:6]1[CH:32]=[CH:31][C:9]([CH2:10][NH:11][C:12]([C:14]2[C:15](=[O:30])[C:16]3[C:17]4[N:18]([CH:29]=2)[CH2:19][C:20](=[O:28])[N:21]([CH3:27])[C:22]=4[CH:23]=[C:24]([C:3]#[C:2][CH2:1][OH:4])[CH:25]=3)=[O:13])=[CH:8][CH:7]=1
Reactant: C#CCO
Reactant: CN1C(=O)Cn2cc(C(=O)NCc3ccc(Cl)cc3)c(=O)c3cc(I)cc1c32
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Product: CN1C(=O)Cn2cc(C(=O)NCc3ccc(Cl)cc3)c(=O)c3cc(C#CCO)cc1c32
Reaction time: 1.5 h

Procedure:
Propargyl alcohol (50 mg), cuprous iodide (50 mg) and a solution of PdCl2(PPh3)2 (1 mL, 0.15 M in THF) are added to a suspension of N-(4-chlorobenzyl)-9-iodo-1-methyl-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide (Preparation 23, 250 mg) in diethylamine (2.0 mL). The reaction is stirred for 90 min and the product is then extracted into chloroform and is chromatographed on silica gel. The desired product is eluted with 20% methanol/chloroform. Physical characteristics: 1H NMR (DMSO-d6) δ3.40, 4.36, 4.56, 5.22, 5.42, 7.36, 7.40, 7.44, 7.88, 8.76, 10.2. HRMS m/z 436.1064 (C23H18ClN3O4).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:9][C:6]1[C:7]([NH2:8])=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=[C:4]([CH3:10])[N:5]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1nc(Cl)c(N)c(-c2ccccc2)n1

Procedure:
The title compound was prepared from 4,6-dichloro-2-methyl-pyrimidin-5-ylamine (500 mg, 2.8 mmol), phenylboronic acid (340 mg, 2.8 mmol), sodium carbonate (920 mg, 8.7 mmol, dissolved in minimal amount of water) and Pd(PPh3)4 (160 mg, 0.14 mmol) in 30 mL of glyme by a procedure similar to example 17, step 1 yielding 380 mg (61%) of a solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([F:13])=[C:8]([F:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].C([Li])(CC)C.[O:19]1[C:23]2([CH2:28][CH2:27][CH:26]([CH:29]3[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]3)[CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20]1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[O:19]1[C:23]2([CH2:24][CH2:25][CH:26]([CH:29]3[CH2:34][CH2:33][C:32]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:7]([F:13])[C:8]=4[F:12])([OH:35])[CH2:31][CH2:30]3)[CH2:27][CH2:28]2)[O:22][CH2:21][CH2:20]1
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)CC1
Reactant: CCCCOc1cccc(F)c1F
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(C2(O)CCC(C3CCC4(CC3)OCCO4)CC2)c(F)c1F
Reaction time: 2 h
Yield: 99.6 %

Procedure:
3-Butoxy-1,2-difluorobenzene (7) (10.0 g) and THF (200 ml) were added to a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00 M, in n-hexane and cyclohexane solution; 64.0 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Successively, 4-(1,4-dioxaspiro[4.5]decan-8-yl)-cyclohexanone (21) (12.8 g) in THF (50 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., while the mixture was allowed to come to 25° C. The reaction mixture was poured into a 3%-aqueous solution of ammonium chloride (100 ml) and ethyl acetate (100 ml) in a vessel and mixed with them. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to leave 4-(1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-butoxy-2,3-difluorophenyl)-cyclohexanol (22) (22.7 g). The resulting compound (22) was a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[O:17][C:18]([CH3:24])=[C:19]([CH2:21][CH2:22][OH:23])[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].O[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[O:17][C:18]([CH3:24])=[C:19]([CH2:21][CH2:22][O:23][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=3)[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1oc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)nc1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1oc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)nc1CCOc1ccc(C=O)cc1
Temperature: -5 °C
Yield: 74.1 %

Procedure:
The compound of Step C 3.61 g (10.9 mmole), 1.53 g (12.5 mmole) 4-hydroxybenzaldehyde, and 3.29 g (12.5 mmole) triphenylphosphine were dissolved in 30 ml tetrahydrofuran with stirring, under nitrogen. The solution was chilled to −5° C. ancl a solution of 1.97 ml (12.5 mmole) diethylcliazodicarboxylate in 10 ml. tetrahydrofuran was added over 10 minutes, with stirring. The reaction exothermed to +3° C. The bath was removed and the reaction stirred under nitrogen for 3 days. The reaction was stripped, dissolved in methylene chloride and placed in the freezer. The diethoxycarbonylhydrazine was then filtered off and the filtrate was chromatographed on 400 ml silica, eluting with a 5% isopropyl alcohol/hexane. The appropriate fractions were bulked and stripped to give 3.52 g (74%) product which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Br[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])=[N:26][CH:27]=1
Reactant: Clc1ccc(Br)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 426 [M+1]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][C@H:36]4[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:38][CH2:37]4)=[O:34])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c11) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow foam.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.[CH3:19][NH2:20]>>[CH3:19][NH:20][C:13]1[CH:12]=[CH:11][C:10]2[CH2:9][NH:8][CH2:17][CH2:16][C:15]=2[N:14]=1
Reactant: Clc1ccc2c(n1)CCN(Cc1ccccc1)C2
Reactant: CN
Product: CNc1ccc2c(n1)CCNC2

Procedure:
6-Benzyl-2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine was reacted with methylamine; deprotection afforded N-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:9][C:8]=1[Cl:22].[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH:26]=[O:27]>C(OCC)C>[C:16]([O:15][C:13]([NH:12][CH2:11][C:10]1[CH:20]=[CH:21][C:7]([CH:26]([OH:27])[CH2:25][C:24]([CH3:29])([CH3:28])[CH3:23])=[C:8]([Cl:22])[CH:9]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)CC=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)c(Cl)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)CC(O)c1ccc(CNC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.1 %

Procedure:
Add butyllithium (8.2 mL, 13.1 mmol) to a solution of 4-bromo-3-chloro-N-(tert-butoxycarbonyl)-benzylamine (1.823 g, 5.7 mmol) in diethyl ether (46 mL) at −78° C. under nitrogen and stir for 30 min. Add 3,3-dimethylbutyraldehyde (1.427 g, 1.7 mL, 14.3 mmol), stir for 30 min at −78° C. and then warm to room temperature. Add water and extract twice the aqueous phase with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate as a yellow oil (274 mg, 14%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:18]=[N:19][C:20](I)=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:10]1.[CH3:24][C@@H:25]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[NH:26]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:18]=[N:19][C:20]([N:26]3[C@H:25]([CH3:24])[CH2:29][CH2:28][S:27]3(=[O:31])=[O:30])=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)nc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)nc3)CC2)c(C)c1
Yield: 29.4 %

Procedure:
Using [4-(2,4-dimethylphenyl)piperazin-1-yl](6-iodopyridin-3-yl)methanone (341 mg) described in Preparation Example 162 and (R)-3-methylisothiazolidine 1,1-dioxide (123 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (102 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11](C(OCC)=O)=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.NO>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccn(-c2ccc(OC)cc2)n1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: NO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-1H-pyrazole-5-[(4-(N-pyrrolidinocarbonyl)phenyl)carboxyamide-3-carboxylic acid (100 mg, 0.23 mmol) in 5 mL of acetonitrile was added triethylamine (0.064 mL, 0.46 mmol) and iso-butyl chloroformate (0.030 mL, 0.23 mmol). After stirring at ambient temperature for 30 min, there was added hydroxylamine hydrochloride (16 mg, 0.23 mmol). The reaction was stirred for 1 h and then the volatiles were removed. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford 28 mg (27%) of the title compound as a white powder. LRMS (ES−): 562.1 (M−H+TFA)−.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1.[NH4+].[Cl-]>C1COCC1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[OH:10])=[CH:15][CH:14]=1
Reactant: COc1ccccc1C=O
Reactant: COc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccccc2OC)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1.5 g of o-anisaldehyde are dissolved in THF and cooled to 0° C. 24.2 ml of 4-methoxyphenylmagnesium bromide (0.5 M in THF) are added to the mixture. The reaction solution is stirred at room temperature overnight and then poured into a 20% NH4Cl solution and extracted with ethyl acetate. 2.63 g of the product are obtained, and this can be employed without further purification.C15H16O3 (244.29) MS (ESI+) 227.05 (M−OH)+
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][C:6]([F:24])=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>>[Cl:23][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[F:24])[N:3]=[C:2]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[C:11]([C:12]1[N:13]=[N:14][NH:15][N:16]=1)=[C:10]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Fc1cc2nc(Cl)c(-c3nnn[nH]3)c(-c3ccccc3)c2cc1Cl
Reactant: CCNCC
Product: CCN(CC)c1nc2cc(F)c(Cl)cc2c(-c2ccccc2)c1-c1nn[nH]n1

Procedure:
The title compound was prepared in analogy to example 102 step C from 2,6-dichloro-7-fluoro-4-phenyl-3-(1H-tetrazol-5-yl)-quinoline (prepared as described in example 107 step B) and diethylamine. Light brown solid. MS (ESI): 397.4 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1)[C:3]([NH:5][C@@H:6]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C@@H:7]([OH:13])[C@H:8]([CH:10]1[CH2:12][CH2:11]1)[OH:9])=[O:4].[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]([S:39]([CH2:42][C@@H:43]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:44](O)=[O:45])(=[O:41])=[O:40])([CH3:38])[CH3:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:15]1([CH2:14][C@H:6]([NH:5][C:3]([C@@H:2]([NH:1][C:44]([C@H:43]([CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:42][S:39]([C:36]([CH3:37])([CH3:38])[CH2:35][NH:34][C:32](=[O:33])[O:31][C:27]([CH3:30])([CH3:28])[CH3:29])(=[O:40])=[O:41])=[O:45])[CH2:21][C:22]2[N:23]=[CH:24][NH:25][CH:26]=2)=[O:4])[C@@H:7]([OH:13])[C@H:8]([CH:10]2[CH2:11][CH2:12]2)[OH:9])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)NCC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 200 mg (0.5 mmol) of (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide, 197 mg (0.5 mmol) of (S)-α-[[[2-(1-tert-butoxyformamido)-1,1-dimethylethyl]sulphonyl]methyl]hydrocinnamic acid, 56 mg (0.5 mmol) of triethylamine, 89 mg (0.5 mmol) of HOBT and 209 mg (0.5 mmol) of HBTU in 15 ml of dimethylformamide is stirred at room temperature for 4 hours. Thereafter, the reaction mixture is evaporated to dryness in a high vacuum, the residue is taken up in 50 ml of ethyl acetate and washed twice with 20 ml of saturated sodium bicarbonate solution. After drying the organic phase over sodium sulphate the solvent is evaporated under reduced pressure. For purification, the residue (420 mg) is chromatographed on 20 g of silica gel using a 95:5:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. After lyophilization from dioxan/water there is obtained tert-butyl [2-[[(S)-2-[[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl)carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-3-phenylpropyl]sulphonyl]-2-methylpropyl]carbamate as a colourless, amorphous powder; MS: 746 (M+H)+.