Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[S:27][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:29][N:30]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[S:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:29][N:30]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Clc1nnc(-c2ccccc2)s1
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nnc(-c3ccccc3)s2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-chloro-5-phenyl-[1,3,4]thiadiazole following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.49 min; Mass spectrum (ESI+): m/z=472 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:18][C@@H:17]2[C@@:13]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:14][CH2:15][C@@H:16]2[F:19])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:24]([O:23][C:21]([NH:20][C@@:13]12[CH2:14][CH2:15][C@H:16]([F:19])[C@@H:17]1[CH2:18][NH:11][CH2:12]2)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@@]12CC[C@H](F)[C@@H]1CN(C(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@]12CC[C@H](F)[C@@H]1CNC2
Yield: 99.4 %

Procedure:
{(1S,5R,6S)-1-tert-Butoxycarbonylamino-6-fluoro-3-azabicyclo[3,3,0]octan-3-yl}carboxylic acid benzyl ester (132 mg, 0.35 mmol) was dissolved in methanol (10 mL). 10% palladium-carbon (M, wet) (50 mg) was added, and the mixture was stirred in a hydrogen atmosphere for three hours. The catalyst was removed by filtration, and then the filtrate was concentrated under reduced pressure. A 1N sodium hydroxide solution was added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate and filtration, the filtrate was concentrated under reduced pressure to give 85 mg of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([CH2:36][OH:37])[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:30]2[CH2:35][CH2:34][CH2:33][CH:32]([CH2:36][OH:37])[CH2:31]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: OCC1CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCC(CO)C3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 3-piperidine methanol (0.022 mL, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[3-(hydroxymethyl)piperidinomethyl]indol-2-yl)isoindolinone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH:10]1([C:16](O)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:16]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:17])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: O=C(O)C1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Product: O=C(NNc1ccc(F)cn1)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a solution of 5-fluoro-2-hydrazinyl-pyridine (for reference procedure see WO 2010 022076, which is incorporated herein by reference in its entirety; 1.00 g, 7.87 mmol), cyclohexane carboxylic acid (1.21 g, 9.44 mmol), and HOBt.H2O (166 mg, 0.787 mmol) at 0° C. under N2 was added EDC (1.81 g, 9.44 mmol), then the mixture stirred at 0° C. for 15 min, and at RT for 17 h. Water was added, then the organics isolated, cooled to 0° C., then the resulting suspension filtered to leave the title compound as a white solid (1.16 g, 62%). 1H NMR (400 MHz, CDCl3): 1.21-1.38 (3H, m), 1.45-1.55 (2H, m), 1.66-1.73 (1H, m), 1.80-1.96 (4H, m), 2.22 (1H, tt, J 11.6, 3.5 Hz), 6.62-6.66 (2H, m), 7.29 (1H, ddd, J 9.2, 7.9, 3.1 Hz), 7.55 (1H, d, J 4.2 Hz), 8.03 (1H, d, J 2.9 Hz).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([NH:11][C:12](SC)=[C:13]([C:16]#[N:17])[C:14]#[N:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CS>CO>[NH2:15][C:14]1[NH:3][N:2]=[C:12]([NH:11][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:13]=1[C:16]#[N:17]
Reactant: NN
Reactant: CSC(NCc1ccccc1)=C(C#N)C#N
Agent: CS
Solvent: O
Solvent: CO
Product: N#Cc1c(NCc2ccccc2)n[nH]c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
24 ml (0.48 mol) of hydrazine hydrate are added dropwise to a solution of 92 g (0.4 mol) of 3-benzylamino-3-methylsulfanyl-2-cyano-acrylonitrile in 400 ml of methanol, the temperature rising to 40° C. The reaction mixture is slowly heated to boiling (e evolution of MeSH!), boiled for 2 hours, cooled to RT and concentrated by evaporation to a residual volume of ≈200 ml. Dilution with diethyl ether, filtration and washing with diethyl ether yield 5-amino-3-benzylamino-1H-pyrazole-4-carbonitrile [Spectrochimica Acta, 47A, 1635 (1991)]; m.p. 150-152° C.; TLC: Rf=0.41 (ethyl acetate).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].CCCCCC.C([Li])CCC.[CH2:21]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1.O>[CH2:21]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([OH:37])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH3:9])[CH2:33][CH2:32]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CSc1ccccc1Br
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CSc1ccccc1C1(O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 6 °C
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
A solution of 2-bromothioanisole (1.05 g) in 20 mL of anhydrous tetrahydrofuran was cooled to -78° C. and treated with 2 mL of 2.5M hexane solution of n-butyl lithium. After the addition was complete the reaction mixture was stirred for 30 minutes and then treated with a solution of N-benzyloxycarbonyl-4-oxopiperidine (1.17 g) in 1 mL of tetrahydrofuran. After stirring at -78° C. for 30 minutes the reaction mixture was allowed to warm to 6° C. and treated with 10 mL of water. Upon extracting with ethyl acetate, drying and evaporation, the organic layer afforded the crude product. This material was purified by chromatography; elution with 6:4 hexane:ethyl acetate afforded the named material (0.27 g); MS: 358; NMR: 1.9-2.1 (b, 4), 2.5 (s, 3), 3.4 (b, 2), 4.1b (b, 2), 5.1 (s, 2), 7.1-7.5 (m, 9).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([Sn](CCCC)(CCCC)CCCC)[CH:6]=[CH:7][CH:8]=1.[CH2:22]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44](Br)[CH:45]=2)[NH:40][CH:39]=1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH2:22]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=3)[CH:45]=2)[NH:40][CH:39]=1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(CO)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(-c3cccc(CO)c3)cc12
Yield: 51.8 %

Procedure:
3-Hydroxymethylphenyltri-n-butylstannane (2.016 g, 5.076 mmol) (see Preparation 25) and 3-(1-benzyloxycarbonylpyrrolidin-2(R)-ylmethyl)-5-bromo-1H-indole (1.902 g, 4.602 mmol) (see Preparation 35B) were reacted together in the presence of tri-o-tolylphosphine, triethylamine and palladium (II) acetate using a procedure similar to that described in Example 1. This yielded the title compound as a white foam (1.050 g). Found: C,75.58; H,6.51; N,5.88; C28H28N2O3.1/12CH2Cl2 requires: C,75.36; H,6.34; N,6.26%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[CH3:26][S:27]C(=N)N.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([S:27][CH3:26])[CH:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CSC(=N)N
Reactant: CC(C)(C)C(=O)C(=Cc1ccc(Cl)cc1)n1cncn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CSC(c1ccc(Cl)cc1)C(C(=O)C(C)(C)C)n1cncn1
Temperature: 25 °C
Yield: 24.9 %

Procedure:
289 g (1 mol) of 1-(4-chlorophenyl)-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one (E,Z isomer mixture) and 139 g (0.5 mol) of S-methylisothiourea sulphate were suspended in 2.5 liters of ethanol and 336 g (4 mol) of sodium bicarbonate were added in portions, while stirring. The mixture was heated under reflux for 4 hours, cooled to room temperature and poured onto water. The organic constituents were extracted with methylene chloride. The organic phase was dried over sodium sulphate, filtered and evaporated down. The resulting oil was caused to crystallize by stirring it with diisopropyl ether, and the crystals were recrystallized from ethanol. 42 g (12% of theory) of 1-(4-chlorophenyl)-4,4-dimethyl-1-methylthio-2-(1,2,4-triazol-1-yl)-pentan-3-one of melting point 145° C. were obtained. ##STR13## Process variant (c):
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10](Cl)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[F:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=1.N1C=CC=CC=1>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:20][N:19]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Nc1ccc(F)cn1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cc(S(=O)(=O)Nc2ccc(F)cn2)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
3-Cyano-4-fluorobenzene-1-sulfonyl chloride (25 g, 114 mmol) was added to a solution of 5-fluoropyridin-2-amine (16.85 g, 150 mmol) and pyridine (23.7 g, 300 mmol) in dichloromethane (500 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After evaporating the solvent the solid was stirred in diluted aqueous hydrochloric acid (2N, 400 mL) for 16 hours. The reaction mixture was filtered, washed with water (200 mL) and dried under high vacuum to afford the title compound as an orange solid (30.9 g, 98%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][O:12][N:13]=[CH:14][C:15]([NH:17][C@H:18]2[C@@H:21]([S:22][CH2:23][CH2:24][OH:25])[NH:20][C:19]2=[O:26])=[O:16])[N:10]=1)=[O:4].[CH2:27]1[O:30][CH:28]1C.C(Cl)(=O)C>CC(N(C)C)=O>[C:28]([O:25][CH2:24][CH2:23][S:22][C@H:21]1[NH:20][C:19](=[O:26])[C@H:18]1[NH:17][C:15](=[O:16])[CH:14]=[N:13][O:12][CH2:11][C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][Cl:1])[S:7][CH:8]=1)(=[O:30])[CH3:27]
Reactant: CC1CO1
Reactant: O=C(C=NOCc1csc(NC(=O)CCl)n1)N[C@@H]1C(=O)N[C@@H]1SCCO
Solvent: CC(=O)N(C)C
Solvent: CC(=O)Cl
Product: CC(=O)OCCS[C@H]1NC(=O)[C@H]1NC(=O)C=NOCc1csc(NC(=O)CCl)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 0.65 g of (3R,4R)-3-[[[(2-chloroacetylamino-4-thiazolyl)(methoxyimino)]acetyl]amino]-4-[[2-(hydroxy)ethyl]thio]-2-azetidinone in 5 ml of dimethylacetamide are added 1 ml of propylene oxide and 0.36 g of acetyl chloride, and the mixture is stirred at 0° C. for 3 hours. After further addition of 0.36 g of acetyl chloride, the mixture is stirred for additional 3 hours. The solvent is then distilled off under reduced pressure to give crystals, which are collected by filtration and washed with methylene chloride. The above procedure gives 0.558 g of (3R,4R)-4-[[2-(acetoxy)ethyl]thio]-3-[[[(2-chloroacetylamino-4-thiazolyl)(methoxyimino)]acetyl]amino]-2-azetidinone.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:22])=[CH:15][CH:14]=1.[O:28]([C@H:36]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:37][CH:38]=[O:39])[Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].S([O-])(O)(=O)=O.[K+]>C1COCC1.CCCCCC>[CH2:19]([O:20][C:21]([NH:23][CH:24]([CH:38]([OH:39])[CH2:37][C@H:36]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:25]([OH:27])=[O:26])=[O:22])[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: CCCCCCCCCCC[C@H](CC=O)O[Si](C)(C)C(C)(C)C
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCCCCCCC[C@H](CC(O)C(NC(=O)OCc1ccccc1)C(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: -75 °C
Yield: 47.9 %

Procedure:
A solution of 3.0 ml of diisopropylamine in 50 ml of THF was treated at 0° C. with 12.0 ml of a solution of 1.6M n-butyllithium in hexane and, after stirring, cooled to -75° C. A solution of 1.26 g of Z-glycine in 10 ml of THF was then added dropwise. The reaction mixture was left to warm to room temperature and again cooled to -75° C. 0.7 g of (R)-3-(t-butyldimethylsiloxy)tetradecanal in 5 ml of THF was then added dropwise at -75° C. The reaction mixture was stirred at -75° C. for 1 hour and at -40° to -50° C. for 1/2 hour, then warmed to 5° C., again cooled to -75° C., poured into dilute potassium hydrogen sulphate solution and extracted with ether. The ether phase was dried, concentrated and chromatographed on silica gel with methylene chloride/methanol. There were obtained 540 mg of (2R/S,3R/S,5R)-2-[1 -(benzyloxy)formamido]-5-(t-butyldimethylsiloxy)-3-hydroxyhexadecanoic acid as a mixture of 4 diastereomers.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[CH2:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].C(N(CC)CC)C.Cl[CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29].Cl>ClCCl>[O:29]=[C:28]1[CH2:27][CH2:26][CH2:25][N:1]1[C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[CH2:5][C:4]([CH3:14])([CH3:15])[C@H:3]1[OH:16]
Reactant: CC1(C)Cc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)Cc2ccc(C#N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of trans-1-amino-3,3-dimethyl-7-cyano-1,2,3,4-tetrahydro-2-napthol (0.5 g), triethylamine (0.5 ml) and 4-chlorobutyrylchloride (0.33 g) in dichloromethane (35 ml) was stirred at room temperature for 1 h. The solution was poured into dilute hydrochloric acid, and the organic layer separated and washed with sodium carbonate solution and dried over magnesium sulphate. Removal of drying agent and solvent gave the crude amide (0.8 g), which was not purified further, but dissolved in dry tetrahydrofuran (60 ml) and sodium hydride (75 mg of 80% dispersion in oil) added portionwise, under nitrogen. The mixture was then stirred at room temperature for 1.5 h, then poured into water and extracted into ethyl acetate. The organic extracts were washed with brine and dried over magnesium sulphate. Removal of drying agent and solvent, followed by crystallisation of the residue from ethyl acetate: 60°-80° petrol (1:1) gave the title compound as colourless microcrystals (0.35 g) having m.p. 203°-4° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[C@:19]([CH2:35][OH:36])([C:31]([O:33][CH3:34])=[O:32])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.N1C=CN=C1.[Si:42](Cl)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]>CN(C=O)C>[CH3:46][C:45]([Si:42]([CH3:44])([CH3:43])[O:36][CH2:35][C@@:19]1([C:31]([O:33][CH3:34])=[O:32])[CH2:18][CH2:17][C@H:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:15][CH:14]=2)[N:20]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])([CH3:48])[CH3:47]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@]1(CO)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@]1(CO[Si](C)(C)C(C)(C)C)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OCc1ccccc1
Reaction time: 36 h
Yield: 74 %

Procedure:
To a solution of 2-methyl 1-(phenylmethyl) (2R,5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-2-(hydroxymethyl)-1,2-pyrrolidinedicarboxylate (D71, 200 mg, 0.4 mmol) and imidazole (60 mg, 0.88 mmol) in dry DMF (1 ml) was added tert-butyl dimethylsilyl chloride and the mixture was stirred for 36 hours. The reaction was quenched with brine, diluted with water and extracted with ethyl acetate. The organic layer was washed with ice cold brine, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel using cyclohexane and ethyl acetate (1:0 to 9:1) to afford the title compound as a colourless oil (180 mg, 74%); Rt (HPLC): 8.50 min; MS: (ES/+) m/z: 608 [MH]+ C34H42FNO6Si requires 607.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][CH2:8][CH:9]([OH:24])[CH2:10][NH:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[CH:17][CH:16]=1)([O-])=O.[H][H].[N+](C1C=C(C=CC=1)OCC1OC1)([O-])=O.C(C1C=CC(OCCN)=CC=1)(=O)N>[Pt]=O.CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[O:7][CH2:8][CH:9]([OH:24])[CH2:10][NH:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[CH:17][CH:16]=1
Reactant: NC(=O)c1ccc(OCCNCC(O)COc2cccc([N+](=O)[O-])c2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Agent: NCCOc1ccc(C(N)=O)cc1
Agent: O=[N+]([O-])c1cccc(OCC2CO2)c1
Solvent: CO
Product: NC(=O)c1ccc(OCCNCC(O)COc2cccc(N)c2)cc1

Procedure:
A solution consisting of 12 g. of 1-(3-nitrophenoxy)-3-[2-(4-carbamoylphenoxy)ethylamino]propan-2-ol (m.p. 127°-129°C.) dissolved in 1000 ml. of methanol was subjected to catalytic hydrogenation over 0.3 g. of platinum oxide at room temperature (~25°C.) and 50 p.s.i. pressure of hydrogen [the 3-nitro starting material was prepared according to the procedure of Example VII from 1-(3-nitrophenoxy)-2,3-epoxypropane and 2-(4-carbamoylphenoxy)ethylamine]. Upon completion of this step, the resultant mixture was filtered and the clear filtrate thereafter evaporated to dryness while under reduced pressure to afford a white residual solid. Recrystallization of the latter material from methanol then gave pure 1-(3-aminophenoxy)-3-[2-(4-carbamoylphenoxy)ethylamino]propan-2-ol, m.p. 149°-157°C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[CH:12]2.CN([CH:23]=[O:24])C>>[Br:6][C:7]1[CH:8]=[C:9]([C:16]([F:19])([F:17])[F:18])[CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH:23]=[O:24]
Reactant: FC(F)(F)c1cc(Br)c2[nH]ccc2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2c(Br)cc(C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Phosphorus oxychloride (1.029 ml, 11.04 mmol) was added dropwise to DMF (8 ml) at 0° C. The mixture was stirred 30 min at 0° C. and 7-bromo-5-(trifluoromethyl)-1H-indole (2.65 g, 10.04 mmol) in DMF (2 mL) was added dropwise. The cooling bath was removed and the reaction was stirred at ambient temperature for 3 hours. The reaction was quenched with ice (5 g) and aqueous sodium hydroxide (1N, 20 mL). The reaction was extracted with ethyl acetate (2×30 mL) and the organic phase was dried with MgSO4 and evaporated. The residue was purified by chromatography on SiO2 with a 5%-60% gradient of ethyl acetate/hexanes. The product 7-bromo-5-(trifluoromethyl)-1H-indole-3-carbaldehyde (2.17 g, 7.43 mmol, 74.0% yield) was obtained as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 10.09 (s, 1H), 9.06 (s, 1H), 8.59 (s, 1H), 8.00 (d, J=3.2 Hz, 1H), 7.72 (d, J=3.0 Hz, 1H). LC/MS (HPLC method 4): tR=3.29 min, 292.06(MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:23])[C:3]=1[CH3:24].[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:30]5[CH:31]=[N:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[C:3]([CH3:24])=[C:4]([CH3:23])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(Cl)c1C
Reactant: COc1ccc(B(O)O)cn1
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
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)cc(C)c2C)cn1
Temperature: 80 °C
Yield: 87.1 %

Procedure:
To N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (100 mg, 0.29 mmol), 6-methoxypyridin-3-ylboronic acid (67 mg, 0.44 mmol) and tetrakis(triphenylphosphine)palladium (0) (34 mg, 0.029 mmol) in 1,2-dimethoxyethane (3.0 mL), 2 M Na2CO3 (438 μL, 0.87 mmol) was added. The reaction mixture was stirred and heated at 80° C. for 15 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(6′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide as a white solid (105 mg, 86.6%). ESI-MS m/z calc. 415.5. found 416.5 (M+1)+. Retention time 1.66 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:34](O)([CH3:36])[CH3:35]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([O:16][CH:34]([CH3:36])[CH3:35])=[O:15])=[CH:10][CH:9]=2)=[CH:20][CH:21]=1
Reactant: CC(Oc1ccc(COc2ccc(Cl)cc2)cc1)C(=O)O
Reactant: CC(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)C(C)Oc1ccc(COc2ccc(Cl)cc2)cc1
Reaction time: 4 h
Yield: 64.9 %

Procedure:
6.1 gm of 2-[4-(4-chlorophenoxy-methyl)-phenoxy]-propionic acid was dissolved in 50 ml of absolute tetrahydrofuran, and 3.2 gm of 1,1'-carbonyldiimidazole were added to the solution. The resulting mixture was heated for a short time and was then allowed to stand at room temperature for 4 hours. Thereafter, the reaction mixture was admixed with 2.4 gm of isopropanol, and the mixture was refluxed for one hour, evaporated in vacuo in a rotary evaporator, and the oily residue was recrystallized from ethanol/water, yielding 4.5 gm (65% of theory) of the ester named in the heading, which had a melting point of 81° C.