Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@H:10]([CH2:11][CH2:12][CH:13]=O)[CH2:9][CH2:8][N:7]1[C@@H:15]([CH3:22])/[C:16](/[CH3:21])=[CH:17]/[CH:18]=[CH:19]\[CH3:20])=[O:5])[CH3:2].[CH2:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[BH3-]C#N.[Na+]>CCO.CCOCC>[CH2:1]([O:3][C:4]([C@@H:6]1[C@H:10]([CH2:11][CH2:12][CH2:13][NH:31][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9][CH2:8][N:7]1[C@H:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:22])=[O:5])[CH3:2]
Reactant: C/C=C\C=C(/C)[C@H](C)N1CC[C@@H](CCC=O)[C@H]1C(=O)OCC
Reactant: NCCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)[C@@H]1[C@H](CCCNCCc2ccccc2)CCN1[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of (2S,3R)-1-((2E,4Z)-(S)-1,2-Dimethyl-hexa-2,4-dienyl)-3-(3-oxo-propyl) pyrrolidine-2-carboxylic acid ethyl ester (1.g, crude) in EtOH (IO mL) is added phenethylamine (0.44 g, 3.65 mmol) at r.t. After stirring at r.t. for 30 min, NaBH3CN (0.3 g, 4.87 mmol) is added in one portion. After stirring at r.t. for 1.5 Hrs, the reaction solution is diluted with 50 mL of ether and washed with 20 mL of brine. The ether layer is concentrated and the crude product is purified by chromatography (CH2Cl2/MeOH: 97/3) to give a pale liquid (405 mg, 30.0%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[O:16][C@H:15]([CH2:17][O:18]CC2C=CC=CC=2)[C@@H:6]1[O:7]CC1C=CC=CC=1)=[O:4].[H][H]>[OH-].[OH-].[Pd+2].CO>[CH3:1][O:2][C:3]([C@H:5]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:6]1[OH:7])=[O:4]
Reactant: COC(=O)[C@H]1O[C@H](COCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@H]1O[C@H](CO)[C@@H]1O

Procedure:
A slurry of 1.01 g of 2,4-anhydro-3,5-bis-O-(phenylmethyl)-D-lyxonic acid methyl ester (prepared by the procedure in Tetrahedron Letters, Vol 31, No. 33, p4787, 1990), 0.253 g of palladium hydroxide on carbon, and 30 ml of methyl alcohol is hydrogenated under a balloon of hydrogen (1 atm.) for2.5 hours. The mixture is filtered through diatomaceous earth, washed with ethyl acetate and ethyl alcohol, and concentrated in vacuo to give 0.460 gof the desired product.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21](C=O)=[CH:20][CH:19]=1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][CH:8]([C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[O:7][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: COc1ccc(C=O)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C2CC(O)=CC(=O)O2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 5 mL of methyl acetoacetate, 2.0 g of NaH 60% dispersion in oil, 25 mL of 2.0M n-butyl lithium in hexane, 7.0 mL of 4-methoxybenzaldehyde and 150 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 159°-162° C. (dec.)). 1H NMR (CDCl3) δ2.91 (dd, 2H), 3.57 (dd, 2H), 3.83 (s, 3H), 5.66 (dd, 1H), 6.93-6.97 (m, 2H), 7.30-7.34 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[CH2:10][CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>>[C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[C:10](=[CH:21][N:22]([CH3:24])[CH3:23])[CH2:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCN=C(c2ccccc2)c2ccccc21
Reactant: COC(OC)N(C)C
Product: CN(C)C=C1CN=C(c2ccccc2)c2ccccc2C1=O

Procedure:
A mixture of 5.2 g (22 mmole) of 3,4-dihydro-1-phenyl-5H-2-benzazepin-5-one and 43 ml of dimethylformamide dimethyl acetal was refluxed for 4 hr. The mixture was concentrated at reduced pressure to dryness. The residue was crystallized with ether to give a yellow solid, mp 131°-133° C. Recrystallization from ether gave yellow prisms, mp 131°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[CH3:10][NH:11][CH3:12].[CH2:13]=O>C(O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:10][N:11]([CH3:13])[CH3:12])[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: Cc1cccc(Cl)c1O
Reactant: C=O
Reactant: CNC
Solvent: CCO
Solvent: O
Product: Cc1cc(CN(C)C)cc(Cl)c1O
Temperature: 25 °C
Yield: 66 %

Procedure:
A solution of 2-chloro-6-methyl phenol (5.0 g, 0.035 mol) in ethanol (25 mL) at room temperature was treated with dimethyl amine (3.95 mL of a 40% solution of dimethylamine in water, 0.035 mol) followed by formaldehyde (2.85 mL of a 37% solution of formaldehyde in water, 0.035 mol). The reaction was heated to reflux for 24 h. At this time, the reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting oil was diluted with water (200 mL) and acidified to pH=2 by addition of a 1N aqueous hydrochloric acid solution. The water layer was extracted with ethyl acetate (300 mL). The ethyl acetate layer was discarded. The water layer was made basic to pH=10 by the addition of a 1N aqueous sodium hydroxide solution and was extracted with ethyl acetate (2×350 mL). The organics were washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting oil was dried under high vacuum overnight to afford 2-chloro-4-dimethylaminomethyl-6-methyl-phenol (2b) (4.62 g, 66%) as an off-white solid; EI(+)-HRMS m/z calcd for C10H14ClNO (M+) 199.0764, found 199.0767. Molecular Weight=199.6822; Exact Mass=199.0764
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:21][N+:18]([O-:20])=[O:19])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccc(CC[N+](=O)[O-])cc1OC
Temperature: 25 °C

Procedure:
In a 1 l. r.b. flask 100 g. (0.6 mole) of 3,4-dimethoxybenzaldehyde, 40 g. (0.52 mole) of ammonium acetate, 50 ml. (0.93 mole) of nitromethane, and 400 ml. of glacial acetic acid were combined and refluxed for 2 hours. The solution was then cooled to room temperature overnight. Yellow crystals were then collected via suction filtration and washed with hexane and ether. 73 g. of desired product were collected with m.p. 133°-134° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][CH3:34])=[O:32])=[CH:21][CH:20]=2)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([S:10][CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:46])C=1>O>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][CH3:34])=[O:32])=[CH:23][CH:24]=2)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([S:10]([CH2:11][CH3:12])=[O:46])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(SCC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CCCCc1nc(S(=O)CC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 77.4 %

Procedure:
500 mg of product obtained in Example 5 with 5 cm3 of methylene chloride and 215 mg of meta chloroperbenzoic acid is agitated for 2 hours at ambient temperature. The mixture is poured into 50 cm3 of water, extracted 3 times with 50 cm3 of methylene chloride, the extracts are dried, filtered and brought to dryness under reduced pressure. The residue (675 mg) is chromatographed on silica (eluant: methylene chloride - acetone (6-4)). 400 mg of the desired product is obtained.
Reaction SMILES: [C:1]([C:4]1[N+:12]([O-])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[OH-].[Na+].[H][H]>O.[Pd]>[C:1]([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)c1c(C(=O)O)ccc[n+]1[O-]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ncccc1C(=O)O

Procedure:
Sixteen grams (88.4 mmol) of 2-acetylnicotinic acid N-oxide (J. Chem. Soc., 1961, 5216) is added to a solution of sodium hydroxide (3.5 g, 88.4 mmol) in 300 ml of water. The pH is adjusted to 9 by the addition of 6N NaOH, and 10% palladium on carbon (1.6 g) is added. The mixture is then hydrogenated until a 20% excess of hydrogen is taken up. The reaction mixture is filtered through Celite, and the pH of the filtrate is adjusted to 2.5 with 6N HCL. The solvent is removed by rotoevaporation and the residue is taken up in methanol. The mixture is filtered and the filtrate is evaporated to give a pale beige solid, 2-acetylnicotinic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH2:16])[CH:15]=1.[C:19](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH:16][CH3:19])[CH:15]=1
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CNc1cc(-c2cc3ccccc3[nH]2)ccc1OC
Temperature: 40 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
In acetone (50 mL) was placed 5-(1H-indol-2-yl)-2-methoxy-phenylamine (2.38 g, 10 mmol). To this was added potassium carbonate (5.53 g, 40 mmol), and to the vigorously stirred mixture was added methyl iodide (1.55 g, 11 mmol). The mixture warmed to 40° C. and stirred for 48 hours. The mixture cooled to room temperature and was filtered free of inorganics. The resulting solution was evaporated in vacuo to give a solid which was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was separated, dried over magnesium sulfate, and evaporated in vacuo to give a tan solid. This solid was purified by flash chromatography over silica gel (5% ethyl acetate/methylene chloride). Evaporation of the appropriate fractions gave 0.68 g of pure compound. MS: M+1=253.1. 1H NMR (DMSO-d6) δ 2.79 (d, J=5.3 Hz, 3H), 3.80 (s, 3H), 5.08-5.12 (m, 1H), 6.69 (s, 1H), 6.83-7.05 (m, 5H), 7.33 (d, J=7.9 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 11.28 (s, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:19][C:20]([C@@H:22]1[CH2:35][C:34]2[CH:33]=[C:32]3[C:27]([O:28][C@@H:29]([C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=4)[C:30](=[O:37])[N:31]3[CH3:36])=[CH:26][C:25]=2[CH2:24][N:23]1[C@H:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:46][CH3:47])=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Cl:55][C:56]1[CH:57]=[C:58]([CH:61]=[CH:62][C:63]=1[Cl:64])[CH2:59]Br.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:19][C:20]([C@@H:22]1[CH2:35][C:34]2[CH:33]=[C:32]3[C:27]([O:28][C@@H:29]([C:38]4[CH:39]=[CH:40][C:41]([O:44][CH2:59][C:58]5[CH:61]=[CH:62][C:63]([Cl:64])=[C:56]([Cl:55])[CH:57]=5)=[CH:42][CH:43]=4)[C:30](=[O:37])[N:31]3[CH3:36])=[CH:26][C:25]=2[CH2:24][N:23]1[C@H:45]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH2:46][CH3:47])=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(F)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(F)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
(S)-3-(4′-Fluoro-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (27 mg, 0.078 mmol) was dissolved in 2 mL of DMF and 3,4-dichlorobenzyl bromide (0.39 mmol) and potassium carbonate (0.39 mmol) were added. The mixture was stirred at room temperature for 8 hours and was poured onto ethyl acetate and 10% sodium carbonate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified over silica (hexanes-ethyl acetate-MeOH, 7-3-0.1) to provide (S)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaz a-anthracene-7-carbonyl]-amino}-3-(4′-fluoro-biphenyl-4-yl)-propionicacid methyl ester (21 mg, LC/MS: m/z 889).
Reaction SMILES: CS[C:3]1[O:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1.[CH:10]1C=C(Cl)C=C(C(OO)=O)C=1.[S:21]([O-:25])([O-])(=[O:23])=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:10][S:21]([C:3]1[O:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1)(=[O:25])=[O:23]
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(C)c(C)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(S(C)(=O)=O)oc1C
Reaction time: 3 h

Procedure:
3 g of 2-methylthio-4,5-dimethyloxazole were dissolved in 100 ml of methylene chloride and 13 g of mCPBA were added at ice temperature. The batch was stirred for three hours and then added to sodium thiosulfate solution. It was neutralized with sodium hydrogencarbonate and the product was extracted with methylene chloride. After drying over magnesium sulfate, the solvent was distilled off and 2 g of crude product were isolated, which it was directly possible to employ further.
Reaction SMILES: O1CCCC1.[N:6]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10][NH:9][CH:8]([C:12]([O:14][CH3:15])=[O:13])[CH2:7]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:30]1[N:35]=[CH:34][N:33]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[C:32](=[O:44])[N:31]=1>O>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][N:33]2[CH:34]=[N:35][C:30]([N:9]3[CH2:10][CH2:11][N:6]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][CH:8]3[C:12]([O:14][CH3:15])=[O:13])=[N:31][C:32]2=[O:44])=[CH:38][CH:39]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=c1nc(Cl)ncn1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1c1ncn(Cc2ccc(Cl)cc2)c(=O)n1
Yield: 43.1 %

Procedure:
To tetrahydrofuran solution (2.3 mL) of 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate (43 mg, 0.17 mmol), sodium carbonate (37 mg, 0.35 mmol) and 4-chloro-1-(4-chlorobenzyl)-1,3,5-triazin-2(1H)-one (45 mg, 0.17 mmol) synthesized in Reference Synthesis Example 11 were added and the resultant solution was stirred at room temperature for 1 day. After completion of the reaction, water was added thereto and extraction with chloroform from the resultant mixture was performed three times. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure and ethyl acetate was added to the obtained residue. The obtained solid was collected by filtration and dried under reduced pressure to obtain the title compound (34 mg, yield 42%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([C:20]([OH:22])=O)[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.Cl.[CH3:32][O:33][C:34](=[O:40])[C@H:35]([CH:37]([CH3:39])[CH3:38])[NH2:36].CCN(CC)CC>C1COCC1.CN1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([C:20]([NH:36][CH:35]([CH:37]([CH3:39])[CH3:38])[C:34]([O:33][CH3:32])=[O:40])=[O:22])[O:17][N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)no1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)no1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 3-(4-(benzyloxy)phenyl)isoxazole-5-carboxylic acid (300 mg) in THF (10 ml), N-methyl morpholine (0.111 ml) was added and reaction mixture was stirred for 10 minutes at RT. Reaction mixture was cooled to −20° C., isobutyl chloroformate (0.132 ml) was added and stirred for 15-20 minutes at −20 to −30° C. L-valine methyl ester hydrochloride (238 mg) neutralized with Et3N (0.198 ml) in THF (5 ml) and added to the above reaction mixture and stirred at −20 to −30° C. for 5 minutes. Then the reaction mixture was gradually allowed to warm to RT over a period of 1 hour. Solvent was evaporated to obtain pale brown solid, which was purified by column chromatography (silica gel, EtOAc—Chloroform) to obtain off white solid, which was crystallized using EtOAc—petroleum ether to obtain the title compound as white solid. Yield: 232 mg (55%); MS (ES+): m/z 409 (M+1); 1H NMR (DMSO-d6; 300 MHz): δ 9.19 (d, 1H), 7.87 (d, 2H), 7.68 (s, 1H), 7.32-7.49 (m, 5H), 7.19 (d, 2H), 5.19 (s, 2H), 4.31 (m, 1H), 3.67 (s, 3H), 2.22 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C@@H:14]([OH:15])[C@@:12]3([CH3:27])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.COC1C=CC([C:36](Cl)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=CC=1.[C:50]([O:53][CH2:54][CH3:55])(=O)C>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:50][O:53][C:54]1[CH:55]=[CH:9][C:10]([N:1]([CH:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:2]2[C:3]3[CH:10]=[CH:9][N:8]([C@@H:11]4[O:17][C@H:16]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[C@@H:14]([OH:15])[C@@:12]4([CH3:27])[OH:13])[C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc3c(N)ncnc32)[C@](C)(O)[C@@H]1O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(N(c2ncnc3c2ccn3[C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@@]2(C)O)C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of the compound from Step G (394 mg, 1.0 mmol) in anhydrous pyridine (5 mL) was added p-methoxyphenylchlorodiphenylmethane (946 mg, 3.06 mmol) and 4-dimethylaminopyridine (DMAP) (123 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 20 h. It was then diluted with ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate solution (3×15 mL) followed by water (2×15mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to an oil. The crude product was purified using column chromatography on silica gel eluting with 5% MeOH in CH2Cl2. The appropriate fractions were collected and evaporated to give the title compound (540 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.C([Si](C)(C)[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:26][O:25]2)=[CH:18][CH:17]=1)(C)(C)C.Cl.[CH3:30][C:31]1[N:32]=[C:33]([N:40]2[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]2)[C:34]2[CH:39]=[CH:38][S:37][C:35]=2[N:36]=1>CC(O)C.CS(C)=O>[OH:25][CH:24]([CH2:26][NH:46][CH:43]1[CH2:42][CH2:41][N:40]([C:33]2[C:34]3[CH:39]=[CH:38][S:37][C:35]=3[N:36]=[C:31]([CH3:30])[N:32]=2)[CH2:45][CH2:44]1)[CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Reactant: Cc1nc(N2CCC(N)CC2)c2ccsc2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CS(C)=O
Product: Cc1nc(N2CCC(NCC(O)COc3ccc(O)cc3)CC2)c2ccsc2n1
Yield: 22 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 1.2 eq. DIEA, 120° C., 48 h), using 200 μmol tert-butyldimethyl(4-(oxiran-2-ylmethoxy)phenoxy)silane and 1-(2-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine HCl-salt to give O-silylated intermediate upon purification by prep. HPLC (reversed phase) and prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 6:4:1) with 22% yield. Product was obtained by deprotection according to SP7 and purification by prep. HPLC (reversed phase) and prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 3:7:1.5) with 25% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[NH:8][C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][N:12]=3)=[N:10][C:6]=2[CH:5]=1)([O-])=O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CO.C(N(CC)CC)C>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:9]2[NH:10][C:6]3[CH:5]=[C:4]([NH2:1])[CH:21]=[CH:20][C:7]=3[N:8]=2)=[N:12]1
Reactant: O=[N+]([O-])c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2nc(-c3n[nH]c4ccccc34)[nH]c2c1
Temperature: 25 °C
Yield: 1019.1 %

Procedure:
A stirred solution of 3-(5-nitro-1H-benzoimidazol-2-yl)-1H-indazole [90.8 mg, Reference Example 233(as)] in methanol (1 ml) was treated with tin chloride (616 mg). The reaction was heated at reflux for 16 hours and then cooled to ambient temperature. The pH of the reaction mixture was adjusted to pH 8 by addition of aqueous sodium bicarbonate and then this mixture was extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate and then evaporated to yield an oil. The crude product was subjected to flash column chromatography on silica eluting with ethyl acetate and 10% triethylamine to give 2-(1H-indazol-3-yl)-3H-benzoimidazol-5-amine (826 mg). MS: 250.31 (M+H)+, 248.31 (M−H)−. HPLC (Method B): RT=2.03 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15])[CH3:6])=[O:4].C(N=[C:23]=[O:24])CCC.C(Cl)(Cl)=O>N1(C2CCCCCCC2)CCCCCCN1.C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]=[C:23]=[O:24])(=[O:16])=[O:15])[CH3:6])=[O:4]
Reactant: CCCCN=C=O
Reactant: COC(=O)C(C)Oc1ccccc1S(N)(=O)=O
Agent: C1CCCC(N2CCCCCCN2)CCC1
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: COC(=O)C(C)Oc1ccccc1S(=O)(=O)N=C=O
Yield: 125.5 %

Procedure:
A mixture of 12.9 g of 2-(1-methoxycarbonylethoxy)benzenesulfonamide, 4.9 g of n-butylisocyanate and 0.1 g of diazabicyclooctane and 130 ml of xylene is refluxed for 30 minutes. Then 10 g of phosgene are passed into the solution at the same temperature over 90 minutes. Excess phosgene is expelled with nitrogen and the solution is then cooled and concentrated in vacuo, affording 17.7 g of 2-(1-methoxycarbonylethoxy)benzenesulfonyl isocyanate in the form of a brownish oil which can be further used without purification.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([N:24]3[CH:30]4[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]4)[CH2:26][CH2:25]3)=[N:21][C:20]=2[CH:33]=1.[CH:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[OH-].[Na+]>ClCCCl>[CH2:34]([NH:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([N:24]3[CH:30]4[CH2:29][CH2:28][N:27]([CH2:32][CH2:31]4)[CH2:26][CH2:25]3)=[N:21][C:20]=2[CH:33]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Nc1ccc2oc(N3CCN4CCC3CC4)nc2c1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: c1ccc(CNc2ccc3oc(N4CCN5CCC4CC5)nc3c2)cc1
Yield: 53.1 %

Procedure:
Sodium triacetoxyborohydride (118 mg, 0.56 mmol) was added to a solution of 4-(5-amino-benzooxazol-2yl)-1,4-diaza-bicyclo[3.2.2]nonane (52 mg, 0.20 mmol, prepared as in Example 39) and benzaldehyde (21 μL, 0.204 mmol) in 1,2-dichloroethane. The resulting mixture was allowed to stir at RT for a period of 3 h, at which time 2 mL of 1 N NaOH solution was added. The aqueous layer was extracted with CHCl3 (3×) and the combined organic layers were washed with water and brine and then dried (Na2SO4), filtered and concentrated. The crude residue was purified by chromatography (Biotage, 25M) eluting with 6% MeOH in CHCl3 containing 1 mL of NH4OH per L of eluent to give 37 mg of the title compound as an oil: 1H NMR (CDCl3, 400 MHz) δ 7.37-7.29 (m, 3H), 7.25-7.22 (m, 2H), 7.00 (d, 1H, J=8.7 Hz), 6.64 (d, 1H, J=2.1 Hz), 6.27 (dd, 1H, J=8.7, 2.1 Hz), 4.47-4.45 (m, 1H), 4.30 (s, 2H), 3.87 (t, 2H, J=5.8 Hz), 3.16-3.09 (m, 4H), 3.01-2.96 (m, 2H), 2.15-2.08 (m, 2H), 1.81-1.73 (m, 2H): 13C NMR (CDCl3, 100 MHz) δ 146.0, 145.1, 142.0, 139.8, 128.8, 127.7, 127.3, 108.8, 106.0, 100.6, 57.3, 50.1, 49.4, 46.5, 44,1, 27.0; MS (Cl) m/z 349.2 (M+1).