Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8].[C:13]([O-])([O-])=O.[K+].[K+].[CH3:19]B1OB(C)OB(C)O1>O1CCOCC1.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>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:11])[CH:5]=[N:6][C:7]=1[CH3:13].[Cl:8][C:7]1[N:6]=[CH:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:3][C:2]=1[CH3:19]
Reactant: O=C([O-])[O-]
Reactant: CB1OB(C)OB(C)O1
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cnc(Cl)c(C)c1
Product: Cc1ncc(C=O)cc1Br
Temperature: 110 °C

Procedure:
To a mixture of methyl 5-bromo-6-chloro-3-pyridinecarboxylate (400 mg, 1.597 mmol), tetrakis(triphenylphosphine)palladium (0) (185 mg, 0.160 mmol), and K2CO3 (331 mg, 2.395 mmol) in dioxane (5 ml), trimethylboroxin (0.446 ml, 3.19 mmol) was added under argon. The reaction mixture was heated at 110° C. for 5 h. The reaction mixture was allowed to cool down, filtered through a pad of silica, and concentrated to give 176 mg of the crude material. Purification by flash chromatography using Flashmaster II, a 5 g spherical silica gel cartridge, and mixtures of hexane and DCM as eluent afforded 76 mg of desired compound and 84 mg of methyl 6-chloro-5-methyl-3-pyridinecarboxylate as by-product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[C:16]3[NH2:20])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+].[CH3:23]COC(C)=O>C(OCC)(OCC)OCC.[Cl-].[Na+].O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][CH3:23])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1nccn1Cc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Reactant: CCOC(C)=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Solvent: O
Product: CNc1nccn1Cc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Product: Cl

Procedure:
A suspension of 1-[1-(3,4-dichloro-phenyl)-1H-imidazol-4-ylmethyl]-1H-imidazol-2-ylamine (0.7 g, 2.3 mmol) in triethyl orthoformate (10 ml) was stirred under reflux for 2 h. The reaction mixture was evaporated to dryness, dissolved in ethanol (10 ml) and cooled in an ice bath. Sodium borohydride (0.091 g, 2.4 mmol) was added and the mixture was allowed to slowly reach 20° C. After 18 h AcOEt and brine was added and the organic phase was separated, dried (Na2SO4) and concentrated. After chromatography [silica, elution with gradient CH2Cl2 to 100% (CH2Cl2/MeOH/aq. NH4OH=90:10:1)] the free base of the title compound was obtained. It was crystallized as the off-white hydrochloride salt (0.25 g; 16%). Mp. >250° C. (MeOH/Et2O), MS: m/e=322 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)[CH3:3].C([Li])CCC.[CH2:15](Cl)[CH2:16][CH2:17][CH:18]=[CH2:19].[O:21]1CCCC1>CCCCCC.[Cl-].[NH4+].C(OCC)C>[CH3:1][CH:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:15](=[O:21])[CH2:16][CH2:17][CH:18]=[CH2:19])[CH3:3]
Reactant: C=CCCCCl
Reactant: CC(C)C1COC(=O)N1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: C=CCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Reaction time: 0.5 h

Procedure:
To a -78° C. solution of 5.0 g of 4-(1-methylethyl)-2-oxazolidinone in 80 ml of tetrahydrofuran is added, dropwise, 15.5 ml of 2.5M n-butyl lithium in hexane. After stirring for 30 minutes, a solution of 4.8 g of 4-pentenyl chloride in 30 ml of tetrahydrofuran is added, dropwise, and the resulting solution is stirred at -78° C. for 3.5 hours. The reaction is diluted with aqueous ammonium chloride and diethyl ether. The organic layer is washed with water, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel, 25% ethyl acetate/petroleum ether) to give 5.8 g of the desired product as a pale yellow oil.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N=[N+]=[N-])cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: [N-]=[N+]=Nc1ccc(CBr)cc1
Temperature: 25 °C
Yield: 104.7 %

Procedure:
A mixture of p-azidotoluene (3.9 g), N-bromosuccinimide (5.5 g) and azobisisobutyronitrile (1.0 g) in carbon tetrachloride (30 ml) was heated under reflux in the dark under nitrogen for 18 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was dissolved in ether (50 ml) and filtered. Evaporation of solvent gave an oil (6.5 g) which was chromatographed on silica gel (200 g, Merck 7734). Elution with petroleum ether (b.p. 40°-60°) gave the title compound as an oil (2.37 g). I.R. (Neat) 2120 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH2:13][OH:14])=[CH:5][NH:6]2.I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH:13]=[O:14])=[CH:5][NH:6]2
Reactant: OCCc1c[nH]c2c(F)ccc(Br)c12
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Product: O=CCc1c[nH]c2c(F)ccc(Br)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
The mixture of 2-(4-bromo-7-fluoro-1H-indol-3-yl)-ethanol (3.00 g, 11.6 mmol) and o-iodoxybenzoic acid (IBX, 9.76 g, 34.9 mmol) in DMSO (60 mL) was stirred overnight at room temperature. The solution was diluted with H2O (100 mL) and the precipitates were filtered and the filter cake was rinsed with EtOAc. The filtrate was extracted with EtOAc (3×150 mL) and the combined organic solution was washed with brine (300 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 25% EtOAc in hexanes) to give 2.48 g (83%) of the title compound as a pale yellow solid. 1H NMR (CDCl3): 300 MHz δ 9.93 (s, 1H), 8.44 (bs, 1H), 7.20 (m, 1H), 7.17 (dd, J=8.40, 4.32 Hz, 1H), 6.80 (dd, J=10.2, 8.40 Hz, 1H), 4.12 (s, 2H).
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[N:5][CH:4]=1.Br[CH2:14][CH2:15][C:16]#[N:17]>CN(C=O)C.CCOC(C)=O.Cl>[C:16]([CH2:15][CH2:14][N:7]1[CH:8]=[N:9][C:10]2[C:6]1=[N:5][CH:4]=[N:3][C:11]=2[NH2:12])#[N:17]
Reactant: N#CCCBr
Reactant: Nc1ncnc2nc[nH]c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCCn1cnc2c(N)ncnc21
Temperature: 80 °C
Yield: 88.9 %

Procedure:
To a suspension of 57% NaH in mineral oil (0.962 g, 22.8 mmol) in dry DMF (100 mL) was added 10 (3.40 g, 24.9 mmol) under nitrogen and the mixture was heated at 80° C. for 1.0 h. A solution of 3-bromopropionitrile (2.81 g, 21.0 mmol) in DMF (5.0 mL) was added at 25° C. and the reaction was heated at 65° C. for 17 h. It was then diluted with EtOAc (250 mL) and 5% aqueous HCl solution (150 mL). The organic layer was separated and then washed with water (4×100 mL). It was dried over MgSO4 (s) and concentrated under reduced pressure. Purification of the residue was carried out by use of column chromatography (EtOAc/hexanes=7.5:2.5) to afford compound 15 (3.510 g, 18.67 mmol) in 75% yield: mp 148-150° C.; Rf(hexanes/EtOAc=1:2) 0.38; UV (EtOH) λmax 260 (ε 13,900); 1H NMR (CD3OD) δ 2.92 (t J=5.8 Hz, 2 H, CH2CN),3.43 (t, J=5.8 Hz, 2 H, CH2N), 8.35 (s, 1 H, HC2), 8.69 (s, 1 H, HC8); MS m/z 188 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4](=[N:12][OH:13])[NH2:5]
Reactant: NO
Reactant: N#Cc1c(F)cccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1c(F)cccc1Cl
Temperature: 72.5 °C
Reaction time: 16 h

Procedure:
A mixture of 15.6 g of 2-chloro-6-fluorobenzonitrile, 9.0 g of hydroxylamine hydrochloride, 7.4 g of sodium carbonate, 50 ml of ethanol and 15 ml of water was stirred at 70-75° C. for 16 h. The solvent was evaporated and the residue was stirred with tertbutyl methyl ether, and the filtrate afforded, after evaporation of the solvent, 17.6 g of the desired product of m.p. 115-120° C.
Reaction SMILES: C1(P(CC)C2C=CC=CC=2)C=CC=CC=1.[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][BH:19][O:18]1.[C:25]([NH:28][C:29]([CH:41]1[CH2:44][C:43]([NH:52][C:53](=[O:60])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)[CH2:42]1)([CH2:37][CH2:38][CH:39]=[CH2:40])[C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:27])[CH3:26]>ClCCl>[C:25]([NH:28][C:29]([CH:41]1[CH2:44][C:43]([NH:52][C:53](=[O:60])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)[CH2:42]1)([CH2:37][CH2:38][CH2:39][CH2:40][B:19]1[O:20][C:21]([CH3:23])([CH3:22])[C:17]([CH3:24])([CH3:16])[O:18]1)[C:30]([NH:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])(=[O:27])[CH3:26]
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)C1CC(NC(=O)c2ccccc2)(c2ccc(Cl)cc2)C1
Reactant: CC1(C)OBOC1(C)C
Agent: CCP(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CC(NC(=O)c2ccccc2)(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
While under argon, a solution of bis(1,5-dicyclooctadiene)diiridium(I)dichloride (58 mg, 0.086 mmol) and diphenylphosphinoethane (68 mg, 0.172 mmol) in dichloromethane (10 mL) was cooled to 0° C., and charged with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.66 mL, 11.44 mmol). After stirring for 15 min, a solution of N-(3-(2-acetamido-1-(tert-butylamino)-1-oxohex-5-en-2-yl)-1-(4-chlorophenyl)cyclobutyl)benzamide (1.46 g, −2.8 mmol) in dichloromethane (35 mL) was added in one portion and the resulting solution was allowed to slowly warm to room temperature. After stirring for 16 h dichloromethane (40 mL) added and the organic layer was washed with water and saturated aqueous sodium chloride. The resulting solution was dried over MgSO4, filtered and concentrated to give the crude product as a mixture of diastereomers. Purification by flash column chromatography (20-80% ethyl acetate in heptane) gave two products. The more lipophilic isomer was isolated and used in the next step (590 mg, 0.924 mmol). 1H NMR (CDCl3, 600 MHz) δ 8.65 (s, 1H), 7.97 (s, 1H), 7.67 (d, J=7.2 Hz, 2H), 7.49-7.53 (m, 3H), 7.40-7.43 (m, 4H), 6.17 (s, 1H), 3.37-3.42 (m, 1H), 3.30-3.34 (m, 1H), 2.72-2.80 (m, 2H), 2.39-2.51 (m, 2H), 2.31 (s, 3), 1.66-1.72 (m, 2H), 1.30 (s, 9H), 1.19 (s, 12H), 1.10-1.17 (m, 2H), 0.83-8.89 (m, 1H), 0.72 (t, J=7.8 Hz, 2H). ESI MS found for C35H49BClN3O5 m/z [638.7/640.8 (M+1), 636.7/638.9 (M−1)]
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: C[C@H](O)C(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A138) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[N:10]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:9]=1)(O)=[O:6]>>[ClH:3].[Cl:3][C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[N:10]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:9]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2c(c1)c(C(=O)O)cn2-c1ccc2ccccc2n1
Product: Cc1ccc2c(c1)c(C(=O)Cl)cn2-c1ccc2ccccc2n1
Product: Cl

Procedure:
15 cm3 of thionyl chloride are added at 22° C. under an argon atmosphere to 0.95 g (2.70 mmol) of 3-carboxy-5-methyl-1-(quinol-2-yl)-1H-indole. After stirring at reflux for 3.5 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated twice with 10 cm3 of dimethoxyethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 1 g of 3-chlorocarbonyl-5-methyl-1-(quinol-2-yl)-1H-indole hydrochloride in the form of a yellow solid which is used directly in the following step.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]2)=[O:7])[CH2:3]1.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C:35](=[N:37]O)[NH2:36]>>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C:35]1[N:37]=[C:24]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[CH2:13][N:8]([C:6]([N:4]3[CH2:5][CH:2]([OH:1])[CH2:3]3)=[O:7])[CH2:9]2)[O:26][N:36]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Reactant: NC(=NO)c1ccc(F)cc1F
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccc(F)cc3F)no2)C1

Procedure:
90.0 mg (0.242 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 47.3 (0.266 mmol) of 2,4-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 35.2 mg (27% of theory).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[NH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:6](=[O:8])[CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:10])[F:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)CCCC(F)(F)F
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Product: O=C(CCCC(F)(F)F)N1C(=O)OC[C@@H]1Cc1ccccc1

Procedure:
Intermediate S-1G was prepared from 5,5,5-trifluoropentanoic acid (3.35 g, 21.46 mmol) and (4S)-4-benzyl-1,3-oxazolidin-2-one (3.80 g, 21.46 mmol) by the general method shown for Intermediate S-1B. Intermediate S-1G (5.67 g, 84%) was obtained as a colorless viscous oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.32-7.39 (2H, m), 7.30 (1H, d, J=7.05 Hz), 7.18-7.25 (2H, m), 4.64-4.74 (1H, m), 4.17-4.27 (2H, m), 3.31 (1H, dd, J=13.35, 3.27 Hz), 3.00-3.11 (2H, m), 2.79 (1H, dd, J=13.35, 9.57 Hz), 2.16-2.28 (2H, m), 1.93-2.04 (2H, m).
Reaction SMILES: FC(F)(F)C(O)=O.O.C(Cl)Cl.[C:12]([O:18][CH2:19][CH2:20][C@H:21]([CH:34]([CH3:36])[CH3:35])[CH2:22][C@H:23]([OH:33])[C@@H:24]([NH2:32])[CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].[NH:37]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C@H:38]([C:46]([NH:48][C@H:49]([C:56](O)=[O:57])[CH2:50][C:51]1[N:55]=[CH:54][NH:53][CH:52]=1)=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH:26]1([CH2:25][C@H:24]([NH:32][C:56]([CH:49]([NH:48][C:46]([C@@H:38]([NH:37][C:59](=[O:60])[O:61][C:62]([CH3:64])([CH3:63])[CH3:65])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:47])[CH2:50][C:51]2[N:55]=[CH:54][NH:53][CH:52]=2)=[O:57])[C@@H:23]([OH:33])[CH2:22][C@@H:21]([CH:34]([CH3:36])[CH3:35])[CH2:20][CH2:19][O:18][C:12](=[O:17])[C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CC(C)[C@@H](CCOC(=O)C(C)(C)C)C[C@H](O)[C@@H](N)CC1CCCCC1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H](CCOC(=O)C(C)(C)C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)C(Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 37 %

Procedure:
In an analogous manner to that described in Example 9, 635 mg (1.78 mmol) of t-butyl [(4S,5S)-4-(cyclohexylmethyl)-5-(S)-2-isopropyl-4-(pivaloyloxy)butyl]-2,2-dimethyl-3-oxazolidinecarboxylate are treated with trifluoroacetic acid/water/methylene chloride for the cleavage of the Boc protecting group with simultaneous opening of the oxazolidine ring and the resulting 347 mg (76%) of (3S,5S,6S)-6-amino-7-cyclohexyl-5-hydroxy-3-isopropylheptyl pivaloate are reacted without further purification with Boc-Phe-His-OH, whereby there are obtained 280 mg (37%) of t-butyl [(S)-α-[[(RS)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-6-(pivaloyloxy)hexyl]carbamoyl]-2-imidazole-4-ylethyl]carbamoyl]phenethyl]carbamate as an amorphous solid, MS: 740 (M+H)+.
Reaction SMILES: C1(C2NN=C(N[C:10]3[N:15]=[C:14]([NH:16][C@H:17](C4C=CC(F)=CC=4)C)[C:13]([CH2:26]NC(=O)CN4CCOCC4)=C[C:11]=3[F:37])C=2)CC1.Cl[C:39]1[N:46]=[C:45]([NH:47][C:48]2[CH:52]=[C:51]([CH3:53])[NH:50][N:49]=2)[C:44]([Cl:54])=[CH:43][C:40]=1[C:41]#[N:42].CC[N:57](C(C)C)C(C)C>CCCCO>[Cl:54][C:44]1[C:45]([NH:47][C:48]2[CH:52]=[C:51]([CH3:53])[NH:50][N:49]=2)=[N:46][C:39]([NH:57][CH:13]([C:14]2[N:15]=[CH:10][C:11]([F:37])=[CH:17][N:16]=2)[CH3:26])=[C:40]([CH:43]=1)[C:41]#[N:42]
Reactant: Cc1cc(Nc2nc(Cl)c(C#N)cc2Cl)n[nH]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNC(=O)CN1CCOCC1)c1ccc(F)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2nc(NC(C)c3ncc(F)cn3)c(C#N)cc2Cl)n[nH]1
Temperature: 160 °C
Yield: 18.2 %

Procedure:
A mixture of 1-(5-fluoropyrimidin-2-yl)ethanamine (Method 72, 0.05 g, 0.35 mmol), 2,5-dichloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]nicotinonitrile (Method 60, 0.06 g, 0.25 mmol), and DIEA (0.12 ml, 0.7 mmol) in n-BuOH (10 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 160° C. for 6 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (DCM-EtOAc=1:1) to give the title compound as a yellow solid (0.017 g, 15%). LC-MS, 373 (M+1). 1H NMR (400 MHz, MeOD) δ 8.75 (s, 2H), 7.45 (s, 1H), 6.40 (s, 1H), 5.45 (br 1H), 2.35 (s, 3H), 1.60 (d, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[NH:3]1.[OH-].[Ca+2].[OH-].[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>C(O)(C)C>[CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:13]=2[Cl:12])[C:4]([CH3:8])=[N:3]1
Reactant: Cc1cc(=O)n(C)[nH]1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 66.7 %

Procedure:
In 65 ml. of isopropanol are suspended 4.48 g. of 1,3-dimethyl-5-pyrazolone and 3 g. of calcium hydroxide and the resulting suspension is heated under reflux for 30 minutes with stirring. After cooling, 8.4 g. of 2,4-dichlorobenzoyl chloride is added dropwise thereto. After completion of the dropwise addition, the mixture is heated under reflux for 2 hours. The solvent is distilled off from the reaction mixture and 15 ml. of water is added to the residue. The mixture is made acidic with 23 ml. of a 2N hydrochloric acid solution and extracted with 60 ml. of chloroform. The chloroform layer is washed with water and the organic phase is separated and dried. The chloroform is distilled off. The residue is recrystallized from ethanol to give 7.6 g. of the desired product as colorless prisms of mp. 165°-166° C. Yield 66.7%
Reaction SMILES: [Br:1][C:2]1[C:3]([S:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=O.Cl.[NH2:19][OH:20]>C(O)(C)C.O>[Br:1][C:2]1[C:3]([S:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=[N:19][OH:20]
Reactant: NO
Reactant: CC(C)(C)Sc1c(Br)cc([N+](=O)[O-])cc1C=O
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)Sc1c(Br)cc([N+](=O)[O-])cc1C=NO
Yield: 150.1 %

Procedure:
A solution of 3-bromo-2-tert-butylsulfanyl-5-nitro-benzaldehyde (1.2 g, 3.8 mmol) and hydroxylamine hydrochloride (1.2 g, 7.7 mmol) in isopropanol (36 mL) and water (8 mL) was heated to 90° C. for 16 h. The reaction mixture was cooled and concentrated to remove isopropanol. Water was added to the residue, followed by saturated sodium bicarbonate solution until the pH was ˜8.0. The residue was extracted with dichloromethane (2×30 mL). The combined organic fractions were dried with sodium sulfate, filtered, and concentrated to afford 1.9 g of the crude title compound which was used without further purification.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:9]=[C:8]([C@@H:10]2[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]2[N+:16]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:19][CH3:20].[H][H]>C(O)C.[Ni]>[F:1][CH:2]([F:21])[O:3][C:4]1[CH:9]=[C:8]([C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH2:16])[CH:7]=[CH:6][C:5]=1[O:19][CH3:20]
Reactant: [H][H]
Reactant: COc1ccc([C@@H]2CC=CC[C@@H]2[N+](=O)[O-])cc1OC(F)F
Agent: [Ni]
Solvent: CCO
Product: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC(F)F

Procedure:
14.6 g of (+/−)-cis-2-difluoromethoxy-1-methoxy-4-(2-nitrocyclohex-4-enyl)benzene are dissovled in 170 ml of ethanol, admixed with 3.0 g of Raney nickel and hydrogenated in an autoclave at a hydrogen pressure of 50 bar for 9 days. The suspension is filtered, the solvent is removed under reduced pressure and the residue is chromatographed over silica gel using a mixture of toluene/dioxane/triethylamine 3/1/0.5. Concentration of the appropriate fractions gives 3.4 g (25.7% of Th.) of the title compound as an oil.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(O[K])(C)(C)C.C(O)(=O)C(O)=O>CN(C)C=O>[C:19]([O:18][C:16]([CH2:15][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CC(C)(C)O[K]
Agent: O=C(O)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c2ccccc2c2ccccc21
Yield: 46.9 %

Procedure:
100 g of carbazole, 117 g of t-butyl bromoacetate, and 67 g of t-butoxy potassium were dissolved in 1,000 g of dimethylformamide. The mixture was reacted overnight at room temperature. After the addition of 300 g of 5 wt % oxalic acid aqueous solution, the reaction mixture was extracted with 2,000 g of n-hexane. Precipitate obtained by crystallization in a mixed solvent of 500 g of dimethylformamide and 500 g of n-hexane was dried under vacuum to obtain 79 g of N-(t-butoxycarbonylmethyl)carbazole as a white solid. This compound is indicated as “other dye (D-2)”.