Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13](=[O:28])[CH2:14][C:15]1[C:16]([F:27])=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([O:25][CH3:26])[CH:21]=[CH:20]2.Br[CH2:30][N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41]>C1COCC1>[CH3:11][O:12][C:13](=[O:28])[CH:14]([C:15]1[C:16]([F:27])=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([O:25][CH3:26])[CH:21]=[CH:20]2)[CH2:30][N:31]1[C:35](=[O:36])[C:34]2[C:33](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:32]1=[O:41]
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: COC(=O)Cc1c(F)ccc2ccc(OC)nc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1c(F)ccc2ccc(OC)nc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of LiHMDS (1M in THF, 9.6 mL) was added at −78° C. a solution of (7-fluoro-2-methoxy-quinolin-8-yl)-acetic acid methyl ester (2.0 g, 8.0 mmol; prepared as in WO 2007/081597) in THF (16 mL) over 10 min. After stirring the resulting orange mixture for 1 h at −78° C., a solution of N-(bromomethyl)phthalimide (1.2 eq.) in THF (16 mL) was added dropwise over 10 min. The mixture was stirred 1 h at −78° C. and then at rt overnight. The yellow solution was quenched with 1N HCl (80 mL) and then extracted with DCM. The combined org layers were washed with water, dried over MgSO4, concentrated and purified by CC (Hept/EA 1:1) to give 1.89 g of a yellow solid which was recrystallized from EA/MeOH/NH4OH (90:10:1) to afford the title intermediate as a colourless solid (924 mg, 28% yield).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:19][CH:18]=1>CN(C=O)C>[CH2:3]([C:7]1[N:8]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[CH:21][CH:22]=2)[C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1.6 g (0.053 mol) of sodium hydride (80%) are suspended under protective gas in 50 ml of DMF, 10 g (0.053 mol) of 2-butyl-5-formyl-4-chloroimidazole (preparation as described in EP 324,377) in 100 ml of DMF are added dropwise at 0° C., the mixture is subsequently stirred for 15 minutes at 0° C., and 18.9 g (0.053 mol) of tert-butyl 2-(4-bromomethylphenyl)-2-cyclopentyl-acetate in 100 ml of DMF are added dropwise. Stirring is continued for 2 hours at 0° C., the solvent is evaporated, the residue is taken up in diethyl ether, the mixture is filtered, and the product is concentrated and then chromatographed over silica gel 60 using dichloromethane. Yield: 16.2 g (66.7% of theory)
Reaction SMILES: C1[O:8][C:6](=O)[CH2:5]OC1=O.[CH3:9][C@H:10]([NH2:78])[C:11]([NH:13][C@H:14]([C:21]([NH:23][C:24]([C@@H:26]([NH:32][C:33]([C@H:35]([NH:43][C:44]([C@@H:46]([NH:57][C:58]([C@@H:60]([NH:62][C:63]([C@H:65]([NH2:77])[CH2:66][C:67]1[CH:76]=[CH:75][C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[CH:68]=1)=[O:64])[CH3:61])=[O:59])[CH2:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[NH:50][CH:49]=1)=[O:45])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])=[O:25])=[O:22])[CH2:15][CH:16]1[N:20]=[CH:19][N:18]=[CH:17]1)=[O:12].[C:79]([OH:91])(=[O:90])[CH2:80][C:81]([CH2:86][C:87]([OH:89])=[O:88])([C:83]([OH:85])=[O:84])[OH:82]>CN1CCCC1=O.O>[CH3:14][N:13]1[C:6](=[O:8])[CH2:5][CH2:10][CH2:11]1.[CH3:9][C@H:10]([NH2:78])[C:11]([NH:13][C@H:14]([C:21]([NH:23][C:24]([C@@H:26]([NH:32][C:33]([C@H:35]([NH:43][C:44]([C@@H:46]([NH:57][C:58]([C@@H:60]([NH:62][C:63]([C@H:65]([NH2:77])[CH2:66][C:67]1[CH:76]=[CH:75][C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[CH:68]=1)=[O:64])[CH3:61])=[O:59])[CH2:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[NH:50][CH:49]=1)=[O:45])[CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])=[O:25])=[O:22])[CH2:15][CH:16]1[N:20]=[CH:19][N:18]=[CH:17]1)=[O:12].[C:79]([O-:91])(=[O:90])[CH2:80][C:81]([CH2:86][C:87]([O-:89])=[O:88])([C:83]([O-:85])=[O:84])[OH:82]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=C1COC(=O)CO1
Agent: C[C@H](N)C(=O)N[C@@H](CC1C=NC=N1)C(=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](C)NC(=O)[C@H](N)Cc1ccc2ccccc2c1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
The following composition was prepared. The polymer solution was composed of 50% by weight of poly(lactide-co-glycolide) (PLGH) with a lactide to glycolide ratio of 75/25 and with an inherent viscosity of 0.20 dL/g dissolved in 50% by weight N-methyl-2-pyrrolidone. The active portion was composed of GHRP-1 and citric acid. The ratio of citric acid to GHRP-1 was about 1.25:1 on a molar basis. The GHRP-1 was dissolved in water; citric acid was added to dissolve; and the solution was filled into a syringe and lyophilized. The contents of the completed syringe were about 80 mg of GHRP-1 and about 20 mg of citric acid.
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[CH:5][C:4]=1[C:8](Cl)=[O:9])[CH3:2].[N+:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[N+:11]([C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:8]([C:4]2[CH:5]=[N:6][O:7][C:3]=2[CH2:1][CH3:2])=[O:9])=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: CCc1oncc1C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Product: CCc1oncc1C(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
(of melting point 139° to 141° C.) from 5-ethylisoxazole-4-carbonyl chloride and 4-nitroaniline.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([S:12]([NH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)(=[O:14])=[O:13])=[CH:7][C:6]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])=[CH:5][C:4]=2[N:3]=1.C([O-])(=[O:30])C.[Na+]>C(O)(=O)C>[CH:16]1([NH:15][S:12]([C:8]2[C:9]3[CH:10]=[CH:11][C:2](=[O:30])[NH:3][C:4]=3[CH:5]=[C:6]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:7]=2)(=[O:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(=O)[O-]
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(Cl)nc2c1
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(=O)[nH]c2c1

Procedure:
A mixture of 2-chloro-N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide (350 mg, 0.86 mmol) and sodium acetate (700 mg, 10 equiv) in acetic acid (10 mL) was refluxed overnight. The mixture was partitioned between sodium bicarbonate solution and ethyl acetate. The organic phase was washed with aqueous sodium bicarbonate solution and dried over sodium sulfate to give N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydroquinoline-5-sulfonamide as a white powder.
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[C:10]([NH:16][C:17]2[N:22]=[C:21]([NH:23][CH:24]3[CH2:26][CH2:25]3)[C:20]3=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]3[N:18]=2)[C:9]=1[Cl:32])[CH3:7])(=O)=O.[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][C:34]1=[O:39]>>[Cl:32][C:9]1[C:8]([CH:6]([N:36]2[CH2:37][CH2:38][NH:33][C:34](=[O:39])[CH2:35]2)[CH3:7])=[CH:13][C:12]([C:14]#[N:15])=[CH:11][C:10]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH:24]2[CH2:25][CH2:26]2)[C:20]2=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]2[N:18]=1
Reactant: O=C1CNCCN1
Reactant: CC(OS(C)(=O)=O)c1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl
Product: CC(c1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl)N1CCNC(=O)C1

Procedure:
This was similarly prepared as Example 678 from 1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)ethyl methanesulfonate and piperazin-2-one (22.74 mg).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[S:12][CH:11]=[C:10]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C1COCC1>C(OCC)(=O)C>[C:25]([O:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[S:12][CH:11]=[C:10]([S:13]([NH2:16])(=[O:15])=[O:14])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1csc(C(=O)c2ccc(O)cc2)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(C(=O)c2cc(S(N)(=O)=O)cs2)cc1
Temperature: 25 °C

Procedure:
58 mg (0.20 mmol) of 5-(4-hydroxybenzoyl)-3-thiophene sulfonamide, 81 mL (1.0 mmol) of pyridine and 94 mL (1.0 mmol) of acetic anhydride were added to 4 mL of THF. The reaction was stirred at rt for 1 1/4 h and then diluted with ethyl acetate. The organic phase was washed with water (2×) followed with brine. The solution was dried over MgSO4 and the solvent removed under vacuum. Flash chromatography utilizing 1:1 hexane/ethyl acetate as the eluant recovered 51 mg of 5-(4-acetoxybenzoyl)-3-thiophene sulfonamide as tan color crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=O)C.C(OC1C=CC(S(C2(C(O)=O)CCN(CC3C=CC=CC=3)CC2)(=O)=O)=CC=1)C1C=CC=CC=1.[OH:69][NH:70]C(C1CCN(CC2C=CC=CC=2)C(S(C2C=CC(OCC3C=CC=CC=3)=CC=2)(=O)=O)C1)=O>CO.C1COCC1>[OH:69][NH:70][C:4]([C:6]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:27]=2)(=[O:21])=[O:20])[CH2:7][CH2:8][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11]1)=[O:3]
Reactant: O=C(NO)C1CCN(Cc2ccccc2)C(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)C1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)CCN(Cc2ccccc2)CC1
Agent: O=C(O)C1(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)CCN(Cc2ccccc2)CC1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NO)C1(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid ethyl ester (5.0 g, 10.1 mmol) was dissolved in MeOH/THF (1:1, 200 ml) and stirred at room temperature for 72 hrs. At the end reaction mixture was concentrated and the product was nuetralised with con. HCl by dissolving it in water (200 mL). After the neutralization reaction mixture was concentrated to dryness. Ice cold water (100 mL) was added to the solid and filtered. The product 4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid was dried at 50° C. and taken to next step with out any purification. Colorless solid. MP: 66-68; Yield: 4.3 g, 91% ; MS: 466 (M+H) Starting from 4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid (4.65 g, 10.0 mmol) and following the procedure outlined in example 83, 1.1 g of 4-(4-Benzyloxy-benzenesulfonyl-1-benzyl-piperidine-4-carboxylic acid hydroxyamide was isolated as a colurless solid. Yield 21%; mp 89° C.; MS: 481.1 1H NMR (300 MHz, DMSO-d6): δ2.27 (m, 3H), 2.76-2.79 (m, 2H), 3.43 (m, 4H),4.30 (s, 2H), 7.14-7.17 (d,2H), 7.50-7.73 (m, 5H), 9.37 (s, 1H), 10.53 (s, 1H), 11.18 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([C:22]([O:24]CC)=[O:23])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)C>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([C:22]([OH:24])=[O:23])[CH:12]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN(C(=O)OCc2ccccc2)C1Cc1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(C(=O)O)CCCN(C(=O)OCc2ccccc2)C1Cc1ccc(OC)cc1

Procedure:
A mixture of 257 g. of diethyl 1-benzyloxycarbonyl-2-(p-methoxybenzyl)-3,3-piperidinedicarboxylate, 35 g. of 86 per cent potassium hydroxide, 530 ml. of ethyl alcohol, and 530 ml. of water was stirred and refluxed for 71/2 hours. The reaction mixture was concentrated under reduced pressure until only water distilled. More water was added to the reaction mixture, which was then extracted twice with diethyl ether. The ether extracts were combined, washed with water, dried, filtered, and the filtrate was concentrated under reduced pressure to recover 108 g. of unhydrolyzed diester starting material. The aqueous layers from the extractions were combined and acidified with concentrated hydrochloric acid, causing separation of an oil. This oil crystallized when shaken from a few ml. of diethyl ether. The mixture was filtered and the solid thus collected was washed with diethyl ether and air-dried. This product was a first crop of 1-benzyloxycarbonyl-2-(p-methoxybenzyl)-3-carbethoxy-3-piperidinecarboxylic acid. By repeating the hydrolysis procedure on the 108 g. of recovered diethyl 1-benzyloxycarbonyl-2-(p-methoxybenzyl)-3,3-piperidinedicarboxylate, using 14.6 g. of 86 per cent potassium hydroxide, 225 ml. of ethyl alcohol, and 225 ml. of water, there was obtained a second crop of 1-benzyloxycarbonyl-2-(p-methoxybenzyl)-3-carbethoxy-3-piperidinecarboxylic acid. The two crops were combined and recrystallized from ethyl alcohol to yield 157 g. of this product as a white solid. When recrystallized from ethyl alcohol, this compound melted at 186°-188°C. (dec.); ir (K.Br) 1740 (ester C=O), 1720 (acid C=O), and 1650 cm-1 (urethane C=O).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH2:13][S:14][C:15]3[N:19]([CH3:20])[CH:18]=[N:17][N:16]=3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:21]Br>C(Cl)(Cl)Cl>[Br:21][C:18]1[N:19]([CH3:20])[C:15]([S:14][CH2:13][C:11]2[O:10][N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:12]=2)=[N:16][N:17]=1
Reactant: BrBr
Reactant: Cn1cnnc1SCc1nc(-c2cccc(Cl)c2)no1
Solvent: ClC(Cl)Cl
Product: Cn1c(Br)nnc1SCc1nc(-c2cccc(Cl)c2)no1
Temperature: 70 °C
Yield: 57.5 %

Procedure:
3-(3-Chloro-phenyl)-5-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole was mixed with 30 ml of chloroform/pyridine(25/1) at room temperature. Then bromine in chloroform (0.5 ml) was added dropwise and the reaction mixture was heated at 70° C. overnight. The reaction mixture was diluted with chloroform and washed with saturated NH4Cl twice and the organic layer was dried with sodium sulfate, concentrated, the residue was triturated with diethyl ether to give the title compound (1.5 g, 57.5%, yellow solid). 1H-NMR(CDCl3) d(ppm): 8.05 (s, 1H), 7.94 (d, 1H), 7.47(d, 1H), 7.43 (t, 1H), 4.66 (s, 2H) and 3.59 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(Nc3cccc(Cl)c3)c2c2ccccc12
Yield: 69.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 3-chloroaniline (83 mg, 0.65 mmol) to provide 191 (96 mg, 68% yield) as a white solid. LC-MS (M+H=322, obsd.=322).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:14][CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][CH:3]=1.[CH3:15][C:16]([S:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].O>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.CCOC(C)=O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]1([CH2:14][CH2:13][CH2:12]1)[C:8]2=[N:21][S:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20]
Reactant: O=C1c2cc(Br)ccc2CC12CCC2
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: CN1c2c([nH]c(N)nc2=O)NCC1CNc1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCC2
Temperature: 25 °C
Yield: 135.3 %

Procedure:
6′-Bromospiro[cyclobutane-1,2′-inden]-1′(3′H)-one (Intermediate 38, 1.1 g, 4.38 mmol), 2-methylpropane-2-sulfinamide (0.96 g, 7.88 mmol), and titanium ethoxide (1.805 mL, 8.76 mmol) were dissolved in methyl THF (20 mL), and heated to reflux overnight. The reaction was allowed to cool to r.t., then it was diluted with EtOAc (150 mL). Water (22 mL) was added dropwise over 10 min under vigorous stirring and then the mixture was left standing without stirring for 1.5 h. The solids were filtered off and the organics were evaporated to give a crude product which was purified by flash chromatography (eluent: heptane/ethylacetate 8:1) to afford the title compound (2.1 g, 77% yield), used as such in the next step: MS (ES+) m/z 354 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[S:14][CH2:13][CH2:12]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.[Cl-].[NH4+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH2:10][CH:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=3)[C:15]=2[S:14][CH2:13][CH2:12]1)[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN(CC1CCSc2[nH]c3ccccc3c21)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(CC1CCSc2c1c1ccccc1n2C(=O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product (333 mg) of the above (1) in dimethylformamide (8 ml) is added a 50% suspension (58 mg) of sodium hydride in mineral oil. The mixture is stirred at room temperature for 1 hour and further at 40°-50° C. for 30 minutes. After addition of a solution of p-chlorobenzoyl chloride (210 mg) in dimethylformamide (2 ml) under ice-cooling, the mixture is further stirred at room temperature for 2 hours. A 10% aqueous solution of ammonium chloride (10 ml) is added thereto under ice-cooling. The mixture is extracted with chloroform. The extract is washed with an aqueous solution of sodium bicarbonate and water, dried and evaporated to give 4-(N-t-butoxycarbonyl-N-methylaminomethyl)-9-(p-chlorobenzoyl)-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole as an oil (533 mg).
Reaction SMILES: [C:1]([CH:5]1CC[CH:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].N([O-])=O.[Na+].F[C:17](F)(F)[C:18]([OH:20])=[O:19]>>[C:1]([CH:5]([CH2:6][CH2:7][CH2:8][OH:11])[CH2:17][C:18]([OH:20])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)C1CCC(O)CC1
Agent: O=N[O-]
Agent: [Na+]
Product: CC(C)(C)C(CCCO)CC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
4-tert-butylcyclohexanol (10 g, 64.1 mmol) was dissolved in trifluoroacetic acid and then NaNO2 (17.09 g, 256.4 mmol) was added to the solution at 0° C. under an air. After the resulting solution was stirred at room temperature for 5 hours, the solvent was removed in vacuo at room temperature and the residue was added into an aqueous 5% NaHCO3. After the solution was treated with methylene chloride, the aqueous solution was acidified with 10% HCl solution followed by extraction with ethyl acetate to give 3-tert-butyl-6-hydroxyhexanoic acid (5.26 g, 41%).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4]1)#[N:2].S(Cl)(Cl)=O.C1(C)C=CC=CC=1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][CH:48]=1)[O:30][C:31]1[CH:45]=[CH:44][C:34]2[N:35]=[C:36]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[O:37][C:33]=2[CH:32]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH:26][C:27]2[CH:48]=[CH:47][CH:46]=[C:29]([O:30][C:31]3[CH:45]=[CH:44][C:34]4[N:35]=[C:36]([NH:38][C:39]([CH:41]5[CH2:42][CH2:43]5)=[O:40])[O:37][C:33]=4[CH:32]=3)[CH:28]=2)=[O:11])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)oc3c2)c1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)oc5c4)c3)c2)CC1
Yield: 66.5 %

Procedure:
Using 3-(1-cyanocyclopropyl)benzoic acid (224 mg, 1.19 mmol), thionyl chloride (1 mL, 13.7 mmol), toluene (5 mL), N-[6-(3-aminophenoxy)-1,3-benzooxazol-2-yl]cyclopropanecarboxamide (131 mg, 424 μmol) produced in Example B1(vii), pyridine (5 mL), and N,N-dimethylpyridine-4-amine (28.1 mg, 230 μmol) as starting materials, and in the same manner as in Example B1(viii), the title compound (135 mg, 66%) was obtained as a colorless solid.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[N:7]12[CH2:15][CH:11]([CH2:12][CH2:13][CH2:14]1)[C:10](=[O:16])[CH2:9][CH2:8]2>ClCCl.[I-].[Zn+2].[I-]>[NH2:6][CH2:5][C:10]1([OH:16])[CH:11]2[CH2:15][N:7]([CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:9]1
Reactant: O=C1CCN2CCCC1C2
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: NCC1(O)CCN2CCCC1C2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Trimethylsilyl cyanide (3 ml) was added dropwise to a stirred solution of 1-azabicyclo[3.3.1]nonan-4-one (2.5 g) and zinc iodide (0.15 g) in dry dichloromethane (20 ml) and the resulting mixture was heated at reflux for 4 hours. The mixture was cooled and the solvent removed at reduced pressure; the residue was dissolved in dry tetrahydrofuran (20 ml) and cooled to 0° C. A solution of lithium aluminium hydride in tetrahydrofuran (18 ml of 1.0M soln) was then added and the resulting solution stirred overnight at room temperature. Water (0.7 ml), followed by 15% sodium hydroxide (aq) (0.7 ml) and water (2.1 ml) were then added and the precipitate removed by filtration. Evaporation of the filtrate yielded the title compound (2.2 g); δH (360 MHz, CDCl3) 1.2-1.3 (2H, m, CH2), 1.34 (1H, m, CHH), 1.41 (1H, m, CHH), 1.6 (2H, m, CH2), 1.7-1.74 (1H, m, CHH), 1.76-1.91 (2H, m, CH2), 2.11-2.16 (1H, m, CHH), 2.67-3.18 (8H, m); m/z 170 (M+).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[H][H]>ClCCl.CO.[Pd]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1C(=O)Cc2cc(N)ccc21

Procedure:
30.0 g (136 mmol) of 1-acetyl-5-nitro-2-indolinone are dissolved in a mixture of 650 ml of dichloromethane and 650 ml of methanol and after the addition of 5 g of 10% palladium on activated charcoal the mixture is hydrogenated for 45 minutes with hydrogen. Then the catalyst is filtered off and evaporated down.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[CH3:18]>>[Cl:10][C:11]1[C:16]([N+:6]([O-:9])=[O:7])=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[CH3:18]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(F)cccc1Cl
Agent: O=S(=O)(O)O
Product: Cc1c(F)ccc([N+](=O)[O-])c1Cl
Temperature: 15 °C
Reaction time: 1.17 h

Procedure:
To a vigorously stirred mixture of sulphuric acid (136 ml) and nitric acid (134 ml), maintained at 15° C. was added dropwise 2-chloro-6-fluorotoluene (100 g) over a period of 30 minutes. The mixture was alllowed to attain room temperature (20° C.), stirred for 70 minutes, then poured onto crushed ice. Solid 2-chloro-6-fluoro-3-nitrotoluene (70 g) was obtained after filtering and drying.