Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]1=[O:13])=[O:5].[C:19](Cl)(=[O:21])[CH3:20].N1C=CC=CC=1>CCOCC>[C:19]([O:12][C:11]1[CH2:10][CH2:9][CH2:8][C:7](=[O:13])[C:6]=1[C:4](=[O:5])[C:3]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=1[Cl:1])(=[O:21])[CH3:20]
Reactant: O=C1CCCC(=O)C1C(=O)c1ccc(Cl)cc1Cl
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OC1=C(C(=O)c2ccc(Cl)cc2Cl)C(=O)CCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(2,4-Dichlorobenzoyl)cyclohexane-1,3-dione (11.4 g, 0.04 mol), acetyl chloride (3.15 g, 0.041 mol) and pyridine (3.2 g, 0.041 mol) were mixed in 100 ml ether and stirred at room temperature for 24 hours. The volatiles were evaporated under reduced pressure, and water and CH2Cl2 were added. The organic layer was then washed three times each with 1N HCl and then 5% Na2CO3, dried with MgSO4 and the solvent evaporated under reduced pressure to yield the product, 8.4 g, 64%. The structure was confirmed as such by nuclear magnetic, infrared and mass spectroscopy.
Reaction SMILES: CC1C=CC(S(O[C@H:12]([CH2:15][CH:16]([CH3:21])[CH2:17][CH2:18][CH:19]=[CH2:20])[CH2:13][CH3:14])(=O)=O)=CC=1.[CH2:22]([O:24][C:25](=[O:41])[CH2:26][N:27]=[C:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[C:29]1([C:28](=[N:27][CH:26]([C@H:12]([CH2:13][CH3:14])[CH2:15][CH:16]([CH3:21])[CH2:17][CH2:18][CH:19]=[CH2:20])[C:25]([O:24][CH2:22][CH3:23])=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C=CCCC(C)C[C@H](CC)OS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCCC(C)C[C@@H](CC)C(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Temperature: 110 °C
Yield: 35.7 %

Procedure:
To a solution of (S)-5-methylnon-8-en-3-yl 4-methylbenzenesulfonate (15 g, 48.3 mmole) and N-(diphenylmethylene)glycinate ethyl ester (15.5 g, 58.0 mmole) in toluene (150 mL) was added LiHMDS (72.5 mL, 72.5 mmole, 1 M solution in THF) at 0° C. The reaction mass was allowed to come to room temperature heated at 110° C. for 2 h. The reaction mass was cooled to room temperature, quenched with water and extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound (7.0 g, 35.7%). The crude compound was taken to the next step without further purification. MS: MS m/z 406.4 (M++1).
Reaction SMILES: C(O[C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[CH:36]1([CH2:39][NH2:40])[CH2:38][CH2:37]1>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:40][CH2:39][CH:36]2[CH2:38][CH2:37]2)=[O:35])=[N:13][C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:15][CH:16]=1
Reactant: NCC1CC1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCC4CC4)n3)cc2CC1

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-cyclopropylmethyl-benzamide was prepared from 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and cyclopropylmethylamine in an analogous manner to Example 1396. Product isolated as a tan solid (30 mg, 47%). m.p.=173-175° C.; LCMS (m/e) 521 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.02 (s, 1H), 8.66 (d, 1H, J=8.4 Hz), 8.09 (s, 1H), 7.54 (d, 1H, J=7.6 Hz), 7.49-7.40 (m, 1H), 7.35 (s, 1H), 7.24 (d, 1H, J=8.0 Hz), 7.16-7.04 (m, 2H), 7.03 (d, 1H, J=8.0 Hz), 6.40-6.30 (m, 1H), 3.56 (t, 2H, J=5.6 Hz), 3.39 (s, 3H), 3.37-3.30 (m, 2H), 2.98-2.83 (m, 4H), 2.82-2.67 (m, 6H), 1.14-1.01 (m, 1H), 0.64-0.55 (m, 2H), 0.35-0.27 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:16])[NH:12][CH2:13][CH2:14][OH:15])[N:10]=2)[CH2:3]1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1.CO>CN(C)C=O>[Si:17]([O:15][CH2:14][CH2:13][NH:12][C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:5][CH:2]([OH:1])[CH2:3]2)[S:7][CH:8]=1)=[O:16])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: O=C(NCCO)c1csc(N2CC(O)C2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCNC(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 3-hydroxy-1-(4-hydroxyethylcarbamoyl-1,3-thiazol-2-yl)azetidine (481.2 mg, 1.98 mmol) (obtained as described in Reference Example 33(3)) in dimethylformamide (24.0 ml) were added t-butyldimethylsilyl chloride (352 mg, 2.3 mmol) and imidazole (116.3 mg, 2.4 mmol) in an ice bath, and the mixture was stirred in the ice bath for 4 hours. After checking the completion of the reaction, methanol was added thereto and the reaction mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (2:3) as the eluant to afford 1-{4-[2-(t-butyldimethylsilyloxy)-ethylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (531.1 mg, yield 75%) as a colorless and transparent syrup.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:14]1([CH:19]=O)[CH2:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl.CCOC(C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:19][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=CC1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CC2CCCC2)CC1

Procedure:
The title compound is synthesized by reductive amination of 1-Boc-piperazine and Cyclopentane-carboaldehyde analogously to the preparation of Example 233 as a colorless oil; ES-MS: M+H=269.2; TLC: Rf=0.45 (DCM/EtOAc=1:1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]4[C:23]([C:24]#[C:25][Si](C)(C)C)=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:13]3)[C:9]2=[O:30])[CH2:4][CH2:3]1.O.[OH-].[Li+].O1CCCC1>O>[C:24]([C:23]1[C:18]([N:14]2[CH2:15][CH2:16][CH2:17][C@@:10]3([C:9](=[O:30])[N:8]([C@H:5]4[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]4)[CH2:12][CH2:11]3)[CH2:13]2)=[N:19][CH:20]=[CH:21][CH:22]=1)#[CH:25]
Reactant: C[Si](C)(C)C#Cc1cccnc1N1CCC[C@]2(CCN([C@H]3CC[C@H](O)CC3)C2=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cccnc1N1CCC[C@]2(CCN([C@H]3CC[C@H](O)CC3)C2=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (5S)-2-(trans-4-hydroxycyclohexyl)-7-{3-[(trimethylsilyl)ethynyl]pyridin-2-yl}-2,7-diazaspiro[4.5]decan-1-one (10 mg, 0.00002 mol, this compound was prepared by using procedures analogous to those described for the synthesis of example 93), lithium hydroxide monohydrate (1.1 mg, 0.000026 mol) in tetrahydrofuran (0.5 mL, 0.006 mol) and a couple of drops of water was stirred at rt for 30 min. The crude reaction mixture was purified by prep-HPLC to afford 7.2 mg of the desired product. LC-MS: 354.2 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[CH:12]2)([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])[CH:12]=[CH:13]1)[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2cc[nH]c12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)Cn1ccc2cccc(O[Si](C)(C)C(C)(C)C)c21

Procedure:
In analogy to the procedure described in example 6 b], 7-(tert-butyl-dimethyl-silanyloxy)-1H-indole (EP 206225 A2) was reacted with ethyl bromoacetate in the presence of cesium carbonate in acetonitrile to give the title compound as colorless liquid.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)[N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C:20]4[CH:48]=[C:47]([N:49]5[CH2:54][CH2:53][N:52]([CH2:55][C:56]6[CH2:61][CH2:60][C:59]([CH3:63])([CH3:62])[CH2:58][C:57]=6[C:64]6[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=6)[CH2:51][CH2:50]5)[CH:46]=[CH:45][C:21]=4[C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([NH:34][CH2:35][CH:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[C:30]([N+:42]([O-:44])=[O:43])[CH:29]=4)(=[O:27])=[O:26])=[O:23])[C:13]=3[N:12]=[CH:11]2)=CC=1.FC(F)(F)C(O)=O>ClCCl>[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C:20]3[CH:48]=[C:47]([N:49]4[CH2:50][CH2:51][N:52]([CH2:55][C:56]5[CH2:61][CH2:60][C:59]([CH3:62])([CH3:63])[CH2:58][C:57]=5[C:64]5[CH:65]=[CH:66][C:67]([Cl:70])=[CH:68][CH:69]=5)[CH2:53][CH2:54]4)[CH:46]=[CH:45][C:21]=3[C:22]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([NH:34][CH2:35][CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[C:30]([N+:42]([O-:44])=[O:43])[CH:29]=3)(=[O:27])=[O:26])=[O:23])[C:13]=2[N:12]=[CH:11]1
Reactant: COc1ccc(C(c2ccc(OC)cc2)n2cnc3c(Oc4cc(N5CCN(CC6=C(c7ccc(Cl)cc7)CC(C)(C)CC6)CC5)ccc4C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)cccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4cccc5[nH]cnc45)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reaction time: 0.5 h

Procedure:
A solution of EXAMPLE 403H (174 mg) and dichloromethane (25 mL) was cooled in an ice bath and 2,2,2-trifluoroacetic acid (25 mL) was added slowly dropwise. The reaction mixture was stirred 30 minutes under nitrogen and the ice bath was removed. The reaction was stirred 18 hours and then concentrated. The crude product was purified by reverse phase chromatography with ammonium acetate buffer in acetonitrile to give the title compound. 1H NMR (400 MHz, pyridine-d5) δ 9.30 (d, 1H), 8.69 (t, 1H), 8.59 (s, 1H), 8.42 (dd, 1H), 7.99 (d, 1H), 7.53 (d, 1H), 7.43 (d, 2H), 7.26 (m, 1H), 7.18 (m, 1H), 7.06 (d, 2H), 6.94 (d, 1H), 6.72-6.66 (m, 2H), 5.53 (m, 2H), 3.98 (m, 2H), 3.32 (m, 2H), 3.18 (t, 2H), 2.03 (m, 4H), 2.76 (s, 2H), 2.25 (m, 2H), 2.13 (m, 4H), 1.97 (s, 2H), 1.83 (m, 1H), 1.60 (m, 2H), 1.40-1.29 (m, 4H), 0.94 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][C:18]1[S:26][C:25]2[C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:23][C:22]([Cl:33])=[N:21][C:20]=2[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([CH2:17][C:18]2[S:26][C:25]3[C:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:23][C:22]([Cl:33])=[N:21][C:20]=3[CH:19]=2)[C@@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
A mixture of (3R,5S)-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.92 g), 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (1 g) and potassium carbonate (1.59 g) in MeCN (10 ml) was heated to reflux for 5 days. The reaction mixture was subsequently cooled, diluted with chloroform, washed with brine and dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by flash column chromatography to yield (3S,5R)-4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester, 170 (1.2 g). Treatment of this compound with HCl in DCM/MeOH produced 2-chloro-6-(2S,6R)-2,6-dimethyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, 171, which was then methylated using 37% formaldehyde solution and sodium borohydride in MeOH, furnishing 172.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][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]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCCN2CCCCC2)c2ccc(C#CCO)cc2c1=O
Temperature: 90 °C
Reaction time: 38 h

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.367 g) is dissolved in DMF (10 mL), and K2CO3 (0.55 g) and N-(3chloropropyl)piperidine hydrochloride (0.408 g) are added. The reaction mixture is heated to 90° C. for 10 h, and then allowed to stir at room temperature for 38 h. Water is added and a precipitate formed. The precipitate is filtered and allowed to dry at room temperature and then under reduced pressure to give 0.187 g of a solid. The solid is dissolved in CHCl3 and filtered to remove 0.045 g of a precipitate. The filtrate is concentrated in vacuo and crystallized from ethyl acetate to give 0.065 g of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][NH:16][C:17]([NH2:19])=[S:18])=[CH:13][CH:14]=2)[N:9]=1)[NH2:3].Cl[CH2:21][C:22](=O)[CH3:23]>C(O)C>[NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][NH:16][C:17]3[S:18][CH:21]=[C:22]([CH3:23])[N:19]=3)=[CH:13][CH:14]=2)[N:9]=1)[NH2:3]
Reactant: CC(=O)CCl
Reactant: NC(=S)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Solvent: CCO
Product: Cc1csc(NCc2ccc(-c3csc(N=C(N)N)n3)o2)n1
Yield: 83.6 %

Procedure:
A suspension of 2-(diaminomethyleneamino)-4-(5-thioureidomethylfuran-2-yl)thiazole (0.70 g) and chloroacetone (0.22 g) in ethanol (15 ml) was refluxed for 4 hours with stirring. The solvent was evaporated in vacuo and the residue was recrystallized from a mixture of methanol and diisopropyl ether to afford 2-(diaminomethyleneamino)-4-[5-(4-methylthiazol-2-yl)aminomethylfuran-2-yl]thiazole (0.66 g).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14](Cl)=[O:15]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:14](=[O:15])[CH2:13][C:12]([CH3:18])([CH3:17])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)CC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 73.7 %

Procedure:
Five grams of 4-nitroaniline was stirred in 25 ml of pyridine and 4.95 g of 3,3-dimethylbutyryl chloride was added. The mixture was stirred 15 hours and poured into ice-water. The resultant solid was collected on a filter and dissolved in 200 ml of ethyl acetate and the solution was treated with activated charcoal and concentrated to yield 6.3 g of 4-nitro-3,3-dimethylbutyrylaminobenzene, m.p. 192°-194°. This material was reduced in 200 ml of methanol, at 3 atmospheres of hydrogen in the presence of 5% Pd/carbon. After removal of the catalyst by filtration, concentration of the filtrate gives 5.3 g of product (3,3-dimethylbutyrylamino)aniline, m.p. 138°-140° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[O:10]1CC[CH2:12][CH2:11]1.[H-].[Na+]>CO.C(OCC)(=O)C>[N:1]1([CH2:12][CH2:11][OH:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1CCOC1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OCCn1cnc2ccccc21
Reaction time: 0.33 h

Procedure:
To a flask were added 2.3 g benzimidazole and 40 ml tetrahydrofuran and the mixture was cooled to 10 C under nitrogen. 1.0 g Sodium hydride were added in portions and the reaction mixture was stirred for 20 minutes. 4.0 g 2-Todoethanol were added and the mixture was heated to 50 C for 16 hours. The mixture was quenched slowly with 50 ml water, extracted twice with ethyl acetate and dried over sodium sulfate. Following filtration and solvent removal, the product was purified by silica gel chromatography using 25% methanol in ethyl acetate. A solid was obtained that was dissolved in a hot mixture of 10% methanol in ethyl acetate, cooled, filtered and dried giving 1.4 g white solid.
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1.[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.O>C1COCC1>[I:13][C:10]1[CH:11]=[CH:12][C:7]([C:17]2([OH:20])[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[CH:8][CH:9]=1
Reactant: Ic1ccc(I)cc1
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2ccc(I)cc2)CCOCC1
Temperature: -78 °C

Procedure:
Under an argon atmosphere, a solution of n-butyllithium (2.59M, in hexane) (8.76 ml) was added dropwise to a solution of 1,4-diiodobenzene (7.49 g) in anhydrous THF (50 ml) at −78° C., and the resulting mixture was stirred at −78° C. for minutes. Tetrahydro-4H-pyran-4-one (2.09 ml) was added dropwise thereto and the resulting mixture was stirred at −78° C. for 1.5 hours. After stirring the mixture for another 3 hours at room temperature, water was added, and the resulting mixture was extracted with ethyl acetate. Organic layer was washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from cyclohexane/ethyl acetate mixed solvent to obtain tetrahydro-4-(4-iodophenyl)-2H-pyran-4-ol (4.12 g).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].BrBr.[NH2:7][C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:11]=[C:10]([C:25]2[N:29]=[CH:28][O:27][N:26]=2)[CH:9]=1.O>CO>[NH2:7][C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:21])[F:22])=[CH:15][C:14]=2[Cl:24])[N:11]=[C:10]([C:25]2[N:29]=[CH:28][O:27][N:26]=2)[C:9]=1[S:1][C:2]#[N:3]
Reactant: Nc1cc(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#CSc1c(-c2ncon2)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: -78 °C
Reaction time: 0.13 h
Yield: 98.2 %

Procedure:
Potassium thiocyanate (1.45 g, 14.9 mmol) was dissolved in 20 ml of dry methanol, and then a methanol (5 ml) solution of bromine (0.28 ml, 5.44 mmol) was added dropwise with stirring at −78° C. over 8 minutes (inner temperature: not higher than −65° C.). After the completion of adding dropwise, the mixture was stirred at −78° C. for 10 minutes and a methanol (15 ml) solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(1,2,4-oxadiazol-3-yl)pyrazole (1.80 g, 4.94 mmol) was added dropwise over 15 minutes. The solution was stirred at −78° C. for 2 hours, warmed to room temperature and then stirred at the same temperature for 2 hours. The reaction mixture was poured into 100 ml of iced water. After stirring for 30 minutes, the deposited crystal was filtered. The resulting crystal was washed with water and then dried under reduced pressure to obtain 2.04 g (4.85 mmol) of the title compound as a colorless crystal. Yield 98.0%.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:10]=[CH:11][C:12]([C:15]#N)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C1C[O:43]CC1>>[CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:43])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cn1
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cn1
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 38 (500 mg, 1.7 mmol) in THF (25 mL) was added 1.6M DIBALH in toluene (3.1 mL, 5.01 mmol) at −78° C. and stirred for 3 h at the same temperature. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (2×50 mL), the combined organic layers were washed with brine (20 mL), dried (Na2SO4) and evaporated. The crude compound was purified by silica gel column chromatography (100-200 mesh, eluted with 20% EtOAc/pet-ether) to obtain compound 39 (350 mg, 69%) as a brown solid. Rf: 0.5 (40% EtOAc/pet-ether); (m/z): 303 [MH]+; 1H NMR (400 MHz, CDCl3): δ 9.85 (1H, S), 8.27 (1H, d, J=2.8 Hz), 7.79 (1H, d, J=8.8 Hz), 7.38-7.20 (10H, m), 7.03 (1H, dd, J=3.2, 8.8 Hz), δ 4.77 (4H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:19]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCC1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 18 h

Procedure:
To a suspension of lithium aluminium hydride (1.41 g) in THF (15 mL) at 0° C. was added piperidine-1,3-dicarboxylic acid 1-tent-butyl ester 3-methyl ester as a solution in THF (10 mL) and the mixture stirred at room temperature for 3 h. The reaction was cooled to 0° C. and quenched by addition of aqueous ammonium chloride and the mixture filtered through celite. The filtrate was diluted with ethyl acetate, washed with water, separated and dried (MgSO4). The solvent was evaporated to give 3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1.25 g). To a solution of this alcohol (422 mg) in THF (8 mL) was added sodium hydride (94 mg; 60% dispersion in mineral oil). After 15 min iodomethane (0.49 mL) was added and the reaction stirred for 18 h. The mixture was then diluted with ethyl acetate and washed sequentially with water, brine, separated and dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography to give 3-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester (414 mg). To a solution of 3-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester (204 mg) in DCM (3 mL) was added 2M hydrogen chloride in diethyl ether and the mixture stirred for 18 h. The solvent was evaporated to give the desired amine (168 mg).