Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][NH:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1.C([O-])(C)(C)C.[K+:36].CCCCCCC>C(O)(C)C>[CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][N-:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1.[K+:36]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CC(C)O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[n-]n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To 40.81 g losartan of Example 1 in 110 ml i-propanol was added 10.86 g of potassium t-butanolate a temperature between 10° C. and 25° C. The reaction mixture clarified. A dense white precipitate was formed when 150 ml of n-heptane was added and stirred at room temperature for 1 hour. It was filtered and washed with 75 ml n-heptane, dried at 50° C. C in vacuo overnight to yield 43.25 g of losartan potassium.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([OH:12])=[CH:8][C:9]=2[CH3:11])[N:4]([CH2:13][CH3:14])[N:3]=1.[CH2:15]=O.[ClH:17].[CH3:18][NH:19][CH3:20]>CN(C)C=O>[ClH:17].[CH3:18][N:19]([CH2:15][C:8]1[C:9]([CH3:11])=[C:10]2[C:2]([CH3:1])=[N:3][N:4]([CH2:13][CH3:14])[C:5]2=[N:6][C:7]=1[OH:12])[CH3:20]
Reactant: CCn1nc(C)c2c(C)cc(O)nc21
Reactant: C=O
Reactant: CNC
Agent: Cl
Solvent: CN(C)C=O
Product: CCn1nc(C)c2c(C)c(CN(C)C)c(O)nc21
Reaction time: 22 h

Procedure:
To a suspension of 28.7 g. of 3,4-dimethyl-1-ethyl-1H-pyrazolo[3,4-b]pyridin-6-ol (0.15 mol.) in 1 1, of dimethylformamide is added 6.75 g. of paraformaldehyde (0.22 mol.) and 13.5 g. of dimethylamine hydrochloride (0.165 mol.) and the mixture is heated at 80° with stirring for 22 hours. Within two hours the starting compounds become dissolved and crystallization of 5-[(dimethylamino)methyl]-3,4-dimethyl-1-ethyl-1H-pyrazolo[3,4-b]pyridin-6-ol, hydrochloride (1:1) begins, increasing after cooling, yield 25.3 g. (59%), m.p. 291°-294°. A sample, recrystallized from dimethylformamide and dried at 140°, melts at 292°-295° (dec.).
Reaction SMILES: [N+]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1)([O-])=O.[BH4-].[Na+].C(O)C>C(OC(=O)C)C.O>[CH2:8]([CH:9]([C:10]#[N:11])[C:12]#[N:13])[C:7]1[CH:14]=[CH:15][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC(C#N)=Cc1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CC(C#N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
4.5 Grams of 4-nitrobenzylidenemalononitrile, prepared according to Example 1, was dissolved in 200 milliliters of ethylacetate. To this was added an aqueous solution of 0.54 gram of sodium borohydride in 5 milliliters of water, and the mixture was stirred at ambient temperature for 1/2 hour. The organic layer was separated, using a separatory funnel, and washed three times with water. The organic extract was dried over anhydrous sodium sulfate, and evaporated to dryness. The crude reaction product was crstallized from ethanol to obtain 3.07 grams(67.5% yield) of the product. IR(nujol) analysis showed bands at 3100, 2950-2850, 2250, 1980, 1595, 1505, 1450, 1440, 1370, 1340, 1290, 1175, 1100, 1010, 885, 860, 845, 755 and 710 cm-1. NMR analysis (CDCl3) showed signals at 8.30 (d, 2H, J=7.8 Hz), 7.56 (d, 2H, J=7.8 Hz), 4.05 (t, 1H, J=6.3 Hz) and 3.42 (d, 2H, J=6.3 Hz) ppm. Elemental analysis: C10H7N3O2 requires: C=59.7; H=3.48; N=20.90%. Found: C=59.62; H=3.39; N=20.81%.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][C@H:7]1[C:20]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])=[O:5])C.[Li+].[OH-]>C1COCC1.O.CO>[C:14]1([S:11]([C@@H:9]2[CH2:10][C@@H:6]([C:4]([OH:5])=[O:3])[C@H:7]([C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])[CH2:8]2)(=[O:13])=[O:12])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)C[C@H]1C(=O)N1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)C[C@H]1C(=O)N1CCOCC1

Procedure:
To a solution of (1R,2R,4S)-4-benzenesulfonyl-2-(morpholine-4-carbonyl)-cyclopentanecarboxylic acid ethyl ester (1.35 mmol) in THF (10 ml) was added a solution of LiOH (3.0 mmol) in water (3 ml) and methanol (3 ml) and stirring was continued at 22° C. until completion of the reaction. The mixture was evaporated and the residue partitioned between ethyl acetate and hydrochloric acid (0.1 N). The organic layer was dried and evaporated to give the title compound as a colorless foam. MS: 368.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH2:38]([S:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:39]#[CH:40].CCO>ClCCl.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.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:40]=[C:39]([CH2:38][S:41][C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCSc1ccccc1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CSc3ccccc3)cc3cc(CN4CCOCC4)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a flame-dried flask under a nitrogen atmosphere is added N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (269 mg) of Preparation 26, PdCl2(PPh3)2 (35 mg), and CuI (12 mg). The flask is back-filled with nitrogen gas and charged with dichloromethane (5 mL), Et3N (0.15 mL), and phenyl propargyl sulfide (0.082 mL). The reaction is stirred at room temperature for 7 days. The reaction mixture is diluted with dichloromethane and partitioned against dilute aqueous sodium bicarbonate. The aqueous phase is extracted with two portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed eluting with 1% to 3% methanol in ethyl acetate. Product containing fractions are combined and condensed to afford a mixture of cyclized and uncyclized materials. To a flask is added the mixture, EtOH (2 mL), and Et3N (0.12 mL). The suspension is heated at 75° C. overnight tightly capped. The reaction mixture is cooled to room temperature, concentrated under reduced pressure, adsorbed onto silica, and flash column chromatographed eluting with 1% to 4% methanol in ethyl acetate. Product-containing fractions are combined and concentrated under reduced pressure to afford a solid. The solid is crystallized from acetonitrile to give 0.16 g of the title compound as light tan product.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:3]=1[NH:4][C:5]1[C:6]([C:17]([OH:19])=[O:18])=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]2=O>CO.O>[Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:3]=1[N:4]=[C:5]1[C:10](=[CH:11]2)[CH:9]=[CH:8][CH:7]=[C:6]1[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1cccc2c(=O)c3cccc(Br)c3[nH]c12
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc2cc3cccc(Br)c3nc12
Yield: 70 %

Procedure:
Reduction of the known [Rewcastle and Denny, Synthesis, 1985, 217] 5-bromo-9-oxoacridan-4-carboxylic acid as above gave 5-bromoacridine-4-carboxylic acid (70%), mp (MeOH/H2O) 327° C. (dec). 1H NMR [(CD3)2SO] δ 7.71 (dd, J=8.3, 7.4 Hz, 1 H, H-2), 7.94 (dd, J=8.4, 7.1 Hz, 1 H, H-7), 8.40 (dd, J=8.7, 0.8 Hz, 1 H, ArH), 8.50 (dd, J=7.3, 1.0 Hz, 1 H, ArH), 8.64 (dd, J=8.3, 1.3 Hz, 1 H, ArH), 8.85 (dd, J=7.1, 1.3 Hz, 1 H, ArH), 9.66 (s, 1 H, H-9), 16.77 (br s, 1 H, COOH). Anal. (C14H8BrNO2) C, H, N, Br.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][CH:24]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:32])[CH2:3][CH2:4]2)=[O:9])[CH:37]=[CH:36][N:35]=1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccnc(Cl)c1)N1CCC(N2CCCC2)CC1
Yield: 17 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 169), 2-chloropyridine-4-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a yellow oil (17%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CN1CCCN(C)C1=O.[CH3:22][C:23]1[C:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)=[N:25][CH:26]=[CH:27][CH:28]=1.[C:39](=O)([O:42]C)[O:40][CH3:41]>C1COCC1>[CH3:41][O:40][C:39](=[O:42])[CH2:22][C:23]1[C:24]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cccnc1-c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)OC
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)Cc1cccnc1-c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12.4 %

Procedure:
A solution of diisopropylamine (4.8 ml, 34 mmol) in dry THF (20 ml) was cooled to 0° C. and n-butyllithium (1.6M in hexanes, 21.3 ml, 34 mmol) was added dropwise. After stirring at 0° C. for 30 mins, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4.1 ml, 34 mmol) was added. After 15 mins a solution of the pyridine (Step 1, 4.033 g, 17 mmol) in dry THF (10 ml) was added. The reaction was stirred for 15 mins at 0° C. then cooled to −78° C. and dimethyl carbonate (3.4 ml, 40 mmol) in dry THF (10 ml) was added. The reaction was allowed to warm to −5° C. and stirred for 1 hr then quenched with saturated NH4Cl solution. The mixture was extracted with EtOAc (×3), the combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (silica, 10-30% EtOAc/hexanes) to give the ester (0.621 g, 12%). 1H NMR (500 MHz, CDCl3) δ: 3.65 (2H, s), 3.67 (3H, s), 7.31-7.34 (1H, m), 7.61-7.62 (2H, m), 7.71-7.75 (3H, m), 8.63-8.64 (1H, m).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.[C-:23]#[N:24].[K+]>Cl.CCOCC.O>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]([N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)[C:23]#[N:24]
Reactant: COc1ccccc1C=O
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: COc1ccccc1C(C#N)N1CCN(c2ccccc2)CC1
Temperature: 0 °C
Yield: 75.6 %

Procedure:
6.5 g (40 mmol) of 1-phenylpiperazine are dissolved in 40 ml of 1N-hydrochloric acid and mixed with a solution of 5.4 g (40 mmol) of 2-methoxybenzaldehyde in 60 ml of ether. The mixture is cooled to 0° C., a solution of 2.5 g (40 mmol) potassium cyanide in 30 ml of water is slowly added dropwise, with stirring, and the mixture is stirred overnight at ambient temperature. Then the organic phase is separated off (any product already precipitated is removed by suction filtration beforehand). The aqueous phase is wasted three times with 50 ml of ether, the organic phases are combined and dried over sodium sulfate. The solvent is eliminated in vacuo and the residue is stirred with cyclohexane and suction filtered. 9.3 g of (2-Methoxyphenyl)-(4-phenylpiperazine-1-yl)-acetonitrile are obtained (76% yield) as an almost colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24][C:25](O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18]2.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](C2CCNCC2)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N:15]2[C:16]([CH2:23][CH2:24][CH2:25][N:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[C:17]3[C:22]([CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:14]2)=[CH:31][CH:30]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: Clc1ccc(N2CCN(CCCc3c4c(nn3-c3ccc(Cl)cc3)CCCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(2-(4-chlorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 12 and 1-(4-chlorophenyl)piperazine were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 2-(4-chlorophenyl)-3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole was obtained, m.p. 129-131° C.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH:16]([CH3:19])[CH2:17][CH3:18])=[CH:11][CH:10]=1)[CH3:6])[CH3:2].I([O-])(=O)(=O)=[O:21].[Na+].CCOCC>CO.O>[CH2:1]([O:3][N:4]=[C:5]([CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH:16]([CH3:19])[CH2:17][CH3:18])=[O:21])=[CH:11][CH:10]=1)[CH3:6])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCON=C(C)COc1ccc(SC(C)CC)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CCON=C(C)COc1ccc(S(=O)C(C)CC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(1-methylpropylthio)phenoxyacetone O-ethyloxime (7.1 mmol) in 10 ml of methanol at 0° is added, dropwise over 5 min., sodium periodate (1.67 g, 7.8 mmol) in 13 ml of water. The mixture is stirred for 3 hours while warming to RT. The reaction is worked up by addition of water and extraction with ether. The combined organic extracts are washed with saturated sodium thiosulfate, with water and with brine, dried and solvent evaporated off to give 4-(1-methylpropylsulfinyl)phenoxyacetone O-ethyloxime.
Reaction SMILES: C1C=CC2N(O)[N:8]=[N:7]C=2C=1.[F:11][C:12]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:13]=1[O:14][C:15]([CH3:20])([CH3:19])[C:16](O)=[O:17].O.NN.C(N(CC)CC)C>C(#N)C>[F:11][C:12]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:13]=1[O:14][C:15]([CH3:20])([CH3:19])[C:16]([NH:7][NH2:8])=[O:17]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(Oc1ccc(F)cc1F)C(=O)O
Agent: NN
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(Oc1ccc(F)cc1F)C(=O)NN
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
HOBt (1.76 g) and WSC•monohydrochloride (2.49 g) were added to a solution of 2-(2,4-difluorophenoxy)-2-methylpropanoic acid (2.34 g) in acetonitrile (27 ml), followed by stirring at room temperature for one hour. This solution was added dropwise to a solution of hydrazine monohydrate (3.25 g) and triethylamine (3.0 ml) in acetonitrile (20 ml) under ice cooling, followed by stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=98:2) to obtain 2-(2,4-difluorophenoxy)-2-methylpropanohydrazide (1.74 g).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1>C(Cl)Cl>[NH2:13][N:17]1[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:16]1=[NH2+:15].[CH3:8][C:3]1[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:14])[C:2]=1[S:9]([O-:12])(=[O:11])=[O:10]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Cc1cccc(N)n1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Cc1cccc(=[NH2+])n1N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of O-(mesitylsulfonyl)hydroxylamine (6.45 g, 30.0 mmol) in DCM (30 mL) was stirred at room temperature, then 2-amino-6-methylpyridine (1.08 g, 10.0 mmol) was added slowly. The reaction mixture was stirred at room temperature for 12 h, and filtered to remove the solvent. A yellow solid was collected which was used for the next step without further purification. ESI MS: m/z 124 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:24]O>>[N:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][CH2:13][CH:14]([C:17]([O:19][CH3:24])=[O:18])[CH2:15][CH2:16]1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
1-(Benzyloxycarbonyl)piperidine-4-carboxylic acid (48.5 g) in methanol (485 ml) was cooled to 0° C. and thionyl chloride (13.34 ml) was added dropwise. The mixture was then refluxed for 20 min (TLC control). When the reaction was complete, the methanol was distilled off, the residue was taken up in water (15 ml) and extracted with ethyl acetate (2×150 ml). The combined organic phases were extracted with water and sat. sodium chloride solution and the extract was dried (Na2SO4) and concentrated in vacuo. Yield: 38 g (67%)
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=Cc1ccc2nc[nH]c2c1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc(NCc2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbaldehyde (146 mg; 1 mmol; 1 eq.), aniline (0.095 ml; 1 mmol; 1 eq.), NaBH(AcO)3 (318 mg; 1.5 mmol; 1.5 eq.) and AcOH (0.095 ml; 1.5 mmol; 1.5 eq.) as described above. Yield: 0.160 g (71%); MS m/z: 224.3 [M+H]+; 1H-NMR (400 MHz, DMSO d6): δ 4.34-4.35 (m, 2H); 6.20.6.21 (m, 1H); 6.45-6.49 (m, 1H); 6.57-6.59 (m, 1H); 6.98-7.02 (m, 1H); 7.17-7.26 (m, 2H); 7.39-7.43 (m, 1H); 7.49-7.52 (m, 2H); 12.34-12.39 (br m, 1H); HPLC (METHOD [A]): rt 8.16 min (97.3%)
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]([C:15]1[C:16]2[CH:17]=[CH:18][NH:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)=[O:14].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>C(O)C>[CH3:25][C:24]([NH:28][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]([C:15]1[C:16]2[CH:17]=[CH:18][NH:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)=[O:14])([CH3:27])[CH3:26]
Reactant: CC(C)(C)N
Reactant: O=C(Nc1ccccc1OCC1CO1)c1cccc2[nH]ccc12
Solvent: CCO
Product: CC(C)(C)NCC(O)COc1ccccc1NC(=O)c1cccc2[nH]ccc12

Procedure:
A solution of 2.8 g of the product from Step C for 1 hour in 40 ml of ethanol and 7.6 ml of tert-butylamine was heated at 80° C. under an inert atmosphere with stirring and after purification by chromatography over silica (eluent:ethyl acetate--triethylamine, 9-1, then chloroform-methanol 5-5), 3.05 g of N-[2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]phenyl]-1H-indol-4-carboxamide were obtained (amorphous beige--colored powder).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:33]2C=CC=C[C:32]=2N=N1.C[N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:52](=[O:53])[C@@H:51]1[N:50]=[CH:55][CH2:54][C@H:32]1[CH3:33]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CC=N[C@H]1C(=O)NCCCC[C@H](N)C(=O)O

Procedure:
Step a) Boc-Lys-OtBu, BOP, NMM, CH2Cl2, RT, 48 hrs; Step b) TFA, RT, 1 hr, ˜100%.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27][P:28]([O:33][CH2:34][CH3:35])([O:30][CH2:31][CH3:32])=[O:29])[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].[OH-].[Li+]>C1COCC1.O>[CH2:31]([O:30][P:28]([CH2:27][CH:26]=[CH:25][CH2:24][CH:4]([CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21])[C:3]([OH:36])=[O:2])([O:33][CH2:34][CH3:35])=[O:29])[CH3:32]
Reactant: CCOP(=O)(CC=CCC(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)C(=O)OC)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(CC=CCC(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)C(=O)O)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.3 %

Procedure:
A mixture of 2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester 4C (33 mg, 0.063 mmol) and lithium hydroxide (44 mg) in a mixture of THF (6 mL) and water (1 mL) was stirred at room temperature for 6 hours. The organic solvent was removed and the residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The aqueous layer was acidified with 2 N HCl and extracted with ethyl acetate. The ethyl acetate extract was concentrated, affording 2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid 4D as an oil (30 mg, 100%); 1H NMR (300 MHz, CDCl3) δ 1.27 (m, 6H), 1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J=6.6 Hz), 3.75 (s, 3H), 4.08 (m, 4H), 5.19 (s, 2H), 5.25 (m, 1H), 5.44 (m, 1H), 5.55 (m, 1H), 5.45 (m, 2H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:23])=[CH:3][CH:2]=1.Cl[CH2:25][S:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.O>CN(C)C=O>[N:30]1[CH:31]=[CH:32][C:27]([S:26][CH2:25][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21](=[O:22])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][S:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[C:13]2=[O:23])=[CH:28][CH:29]=1
Reactant: ClCSc1ccncc1
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCCSc1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2ccccc2n(CSc2ccncc2)c(=O)n1CCCCSc1ccncc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
To a solution of 491 mg (1.5 mmol) of 3-[4-(4-pyridylthio)butyl]quinazoline-2,4(1H,3H)-dione and 287 mg (1.8 mmol) of 4-chloromethylthiopyridine in 15 ml of dimethylformamide, 0.27 ml (1.8 mmol) of 1,8-diazabicyclo-[5.4.0]-7-undecene was added, and the mixture was stirred at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was purified by flash column chromatography (eluent: ethyl acetate/hexane=2:1 to 4:1 to ethyl acetate) to give 0.315 g of the desired product (46.7% yield, colorless oil).