Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][C:17]([C:23]([O:25]CC)=[O:24])=[CH:16][C:15]=3[CH:28]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].O.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1.C(O)CO>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:20](=[O:21])(=[O:22])[CH2:19][CH2:18][C:17]([C:23]([OH:25])=[O:24])=[CH:16][C:15]=3[CH:28]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCS3(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: OCCO
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Ethyl 7-(4-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxlate (1.0 g, 2.497 mmol) was dissolved in 15 ml of a mixed solution of tetrahydrofuran/ethylene glycol =2/1. Crystals were formed by adding 8.5 ml of water. Potassium carbonate (690 mg, 4.994 mmol) was added and the mixture was heated under reflux for 3.25 hours. Under reflux, 3.5 ml of a 3N hydrochloric acid was dropped to form crystals. After cooling, the mixture was stirred at 20-30° C. for 45minutes and for 1 hour while cooling in ice. After filtration, the residue was washed with 10 ml of a mixed solution of tetrahydrofuran/methanol/water=1/1/3. After vacuum drying (40° C.), 858 mg (Yield 92%) of 7-(4-propoxyphenyl)-1, 1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid was obtained as pale yellowish white crystals.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:9][CH:8]=1)[C:4](O)=[O:5].C1C2C(=CC=CC=2)C=CC=1COC1C=C(C([O:49][N:50]=[CH:51]C(O)=O)CCCC2C=CC=CC=2)C=CC=1.N>>[OH:49][N:50]([CH3:51])[C:4](=[O:5])[CH:3]([O:2][CH3:1])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:9][CH:8]=1
Reactant: O=C(O)C=NOC(CCCc1ccccc1)c1cccc(OCc2ccc3ccccc3c2)c1
Reactant: COC(C(=O)O)c1ccc(OCc2ccccn2)cc1
Agent: N
Product: COC(C(=O)N(C)O)c1ccc(OCc2ccccn2)cc1

Procedure:
The desired material was prepared according to the procedures described in Example 5 substituting 2-methoxy-2-[4-(pyrid-2-ylmethoxy)phenyl]acetic acid for {[1-(3-[2-naphthylmethoxy]phenyl)-4-phenylbutyl]oximino}acetic acid. 1H NMR (DMSO-d6, 300 MHz) δ 3.07 (s, 3H), 3.12 (s, 3H), 5.18 (s, 2H), 5.23 (s, 1H), 7.0 (d, J=7Hz, 2H), 7.3 (d, J=7Hz, 2H), 7.34 (m, 1H), 7.5 (d, J=7Hz, 1H), 7.83 (dt, J=7Hz, 2Hz, 1H), 8.04 (m, 1H), 9.9 (bs, 1H). IR (CDCl3): 3620, 3500, 1640, 1610 cm-1. MS (DCI/NH3) m/e 301 (M+H)+. Analysis calcd for C16H18N2O4 ·0.5 H2O: C, 61.73; H, 6.15; N, 9.04. Found: C, 61.96; H, 5.77; N, 8.86. (In some examples O-acylated products were isolated.)
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]([O:21]C)=[O:20].[OH-].[K+]>O.C1COCC1>[Br:1][C:2]1[C:3]2[O:10][C:18]([C:19]([OH:21])=[O:20])=[CH:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1O
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2cccc(Br)c2o1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
10 g (49.75 mmol) of 3-bromo-2-hydroxybenzaldehyde and 1.84 g (4.97 mmol) of tetra-N-butylammonium iodide are, together with 27.5 g (199.0 mmol) of anhydrous potassium carbonate, initially charged. 24.3 g (223.86 mmol) of methyl chloroacetate are added. The reaction mixture is heated at 130° C. for 4 h and then cooled to 0° C. using an ice bath. 100 ml of THF and 16.75 g (298.5 mmol) of potassium hydroxide in 100 ml of water are added, the mixture is then stirred at 40° C. for 4 h. The solvent is removed under reduced pressure. The residue is diluted with water and acidified with conc. hydrochloric acid. The product is purified on silica gel 60 (mobile phase: toluene/ethyl acetate/acetic acid 40:10:1). The solvent is removed under reduced pressure. Any last solvent residues are finally removed under high vacuum. Fine purification is carried out by preparative HPLC. 303 mg (2.5% of theory) of the title compound are isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[CH:14]=[N:15][NH:16][C:17]=2[CH2:18]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:23]([O:26][C:27](Cl)=[O:28])[CH:24]=[CH2:25]>>[CH2:23]([O:26][C:27]([N:15]1[N:16]=[C:17]2[C:13]([CH:12]3[N:11]([S:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)(=[O:9])=[O:10])[CH:19]([CH2:18]2)[CH2:20][CH2:21][CH2:22]3)=[CH:14]1)=[O:28])[CH:24]=[CH2:25]
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cn[nH]c1C2
Reactant: C=CCOC(=O)Cl
Product: C=CCOC(=O)n1cc2c(n1)CC1CCCC2N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared by acylation of 12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene using allylchloroformate
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][NH:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]#[C:30][CH3:31]>CN(C)C=O.C(OCC)(=O)C>[C:16]([O:15][C:13]([N:10]1[CH2:9][CH2:8][C:7]2([O:20][CH:3]([CH2:2][OH:1])[CH2:4][N:5]([CH2:28][C:29]#[C:30][CH3:31])[CH2:6]2)[CH2:12][CH2:11]1)=[O:14])([CH3:17])([CH3:19])[CH3:18]
Reactant: CC#CCBr
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(CO)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCN1CC(CO)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 45 °C
Yield: 70.3 %

Procedure:
Tert-butyl 10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.35 g, 4.71 mmol), K2CO3 (3.26 g, 23.6 mmol) and 1-bromobut-2-yne (495 μL, 5.66 mmol) were combined in N,N-dimethylformamide (15 mL) and heated for 48 h at 45° C. under nitrogen. The reaction mixture was diluted with ethyl acetate (150 mL) and filtered. The filtrate was washed with water, 50% saturated sodium bicarbonate solution, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The desired fractions obtained from silica gel chromatography (5-20% methanol/dichloromethane) were combined and concentrated, then brought up in ethyl acetate, filtered and concentrated in vacuo to provide tert-butyl-8-but-2-ynyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.12 g, 3.31 mmol, 70%). ESI-MS m/z calc. 338.2. Found 339.3 (M+1)+; Retention time: 0.86 minutes (3 min run).
Reaction SMILES: N1(CCO[C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]([C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)=[CH:19][N:20]=3)=[CH:11][CH:10]=2)CCCC1.COC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.B(Br)(Br)Br>C(Cl)Cl.CO>[C:12]1([NH:15][C:16]2[S:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=3)=[CH:19][N:20]=2)[CH:11]=[CH:10][CH:9]=[CH:14][CH:13]=1
Reactant: Oc1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Agent: BrB(Br)Br
Agent: COc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc(-c2cnc(Nc3ccccc3)s2)cc1

Procedure:
The title compound is prepared as described in Example 7 for 4-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-thiazol-5-yl}-phenol but starting from [5-(4-methoxy-phenyl)-thiazol-2-yl]-phenyl-amine and using 2 equivalents of BBr3. Title compound: ES-MS: 269.0 [M+H]+; single peak at tR=6.65 min (System 1); Rf=0.05 (CH2Cl2/MeOH, 98/2).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([CH2:23][CH:24]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][C:19]=2[CH:37]=1)#[N:14].[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[CH2:50]O)=[O:44])([CH3:41])([CH3:40])[CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[CH2:50][O:36][C:33]1[CH:32]=[CH:31][C:30]([CH:24]([CH2:23][C:21]2[O:22][C:18]3[CH:17]=[CH:16][C:15]([C:13]#[N:14])=[CH:37][C:19]=3[CH:20]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:35][CH:34]=1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
1.04 g of diethyl azodicarboxylate was added to 300 ml of a tetrahydrofuran solution containing 1 g of ethyl 3-(5-cyano-2-benzofuranyl )-2-(4-hydroxyphenyl)propionate, 1.2 g of (2S)-1-tert-butoxycarbonyl-2-pyrrolidinemethanol and 1.56 g of triphenylphosphine, and the thus prepared mixture was stirred at room temperature for 18 hours. To the resulting reaction solution were added 0.6 g of (2S)-1-tert-butoxycarbonyl-2-pyrrolidinemethanol, 0.78 g of triphenylphosphine and 0.52 g of diethyl azodicarboxylate, followed by additional stirring at room temperature for 18 hours. Thereafter, the reaction solution thus obtained was concentrated to dryness, and the resulting residue was purified by subjecting it to silica gel column chromatography using a toluene/ethyl acetate mixture as an eluant. In this way, 790 mg of the title compound was obtained in the form of colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](=[O:32])[C:22]5[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=5)([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.O1CCOCC1.CO.ClCCl>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:22]5[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][N:23]=5)=[O:32])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][NH:17][CH2:16][CH2:15]4)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2cc(C(F)(F)F)ccn2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1cc(C(F)(F)F)ccn1)[C@@]12CNCCC1=Cc1c(cnn1-c1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 69.1 %

Procedure:
(R)-tert-butyl 1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (2 g, 2.65 mmol) was dissolved in a solution of HCl in dioxane (4M) (13.27 ml, 53.1 mmol) and the reaction mixture was stirred at room temperature for 45 minutes. The solvent was removed in vacuo to give an orange gum. This was treated with a mixture of 10% methanol (containing 1% of ammonia)/dichloromethane until complete dissolution of the gum, then the solvent was removed in vacuo to give an orange solid. The crude product was purified by chromatography on silica gel (gradient: 0-10% methanol (containing 1% of ammonia) in dichloromethane) to give (R)-(1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (810 mg) as a pale orange solid. LCMS (Method F, ES-API): RT 1.41 min, m+H=443.2.
Reaction SMILES: C([S:4][CH2:5][C:6]1([CH3:24])[C:21](=[O:22])[N:9]2[CH2:10][CH2:11][CH2:12][CH:13]([C:14]([O:16]C(C)(C)C)=[O:15])[N:8]2[C:7]1=[O:23])(=O)C>FC(F)(F)C(O)=O>[SH:4][CH2:5][C:6]1([CH3:24])[C:21](=[O:22])[N:9]2[CH2:10][CH2:11][CH2:12][CH:13]([C:14]([OH:16])=[O:15])[N:8]2[C:7]1=[O:23]
Reactant: CC(=O)SCC1(C)C(=O)N2CCCC(C(=O)OC(C)(C)C)N2C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(CS)C(=O)N2CCCC(C(=O)O)N2C1=O
Reaction time: 1 h
Yield: 42.8 %

Procedure:
A solution of 0.71 g of tert.butyl 2-acetylthiomethyl-hexahydro-2-methyl1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (diastereomer A) in 10 ml of trifluoroacetic acid was left to stand at room temperature for 1 hour. The mixture was evaporated to dryness and the residue was stirred under nitrogen with 50 ml of 50:50 mixture of water and concentrated aqueous ammonia for 2 hours. The mixture was acified to pH 1 with hydrochloric acid, saturated with sodium chloride and extracted with chloroform. The chloroform extracts were dried over sodium sulfate and evaporated. The residue was recrystallized from ethyl acetate/hexane to give 0.22 g (43%) of hexahydro-2-mercaptomethyl-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (diastereomer A) in the form of white crystals having a melting point of 209°-211° C.
Reaction SMILES: [CH3:1][C@:2]1([CH2:14][OH:15])[O:7][C:6]2=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]2[CH2:4][CH2:3]1.[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.[H-].[Na+]>>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:15][CH2:14][C@@:2]2([CH3:1])[O:7][C:6]3=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]3[CH2:4][CH2:3]2)=[CH:19][CH:18]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C[C@@]1(CO)CCn2cc([N+](=O)[O-])nc2O1
Agent: [H-]
Agent: [Na+]
Product: C[C@@]1(COCc2ccc(Br)cc2)CCn2cc([N+](=O)[O-])nc2O1
Yield: 61 %

Procedure:
Alkylation of (S)-alcohol 162 with 4-bromobenzyl bromide (1.35 equiv.) and NaH (1.55 equiv.) as in Example 2UU above for 3 h, followed by chromatography of the product on silica gel, eluting with CH2Cl2 (foreruns) and then with 1% EtOAc/CH2Cl2, gave (7S)-7-{[(4-bromobenzyl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (163) (373 mg, 61%) as a white solid: mp (CH2Cl2/hexane) 159-161° C.; 1H NMR (CDCl3) δ 7.46 (dt, J=8.4, 2.1 Hz, 2H), 7.39 (s, 1H), 7.12 (dt, J=8.4, 2.1 Hz, 2H), 4.50 (s, 2H), 4.09 (ddd, J=12.5, 7.0, 5.8 Hz, 1H), 4.01 (ddd, J=12.5, 7.1, 5.9 Hz, 1H), 3.62 (d, J=10.2 Hz, 1H), 3.58 (d, J=10.2 Hz, 1H), 2.37 (ddd, J=14.4, 7.1, 5.9 Hz, 1H), 2.10 (ddd, J=14.5, 7.0, 5.9 Hz, 1H), 1.46 (s, 3H); [α]D27−32.0° (c 1.00, CHCl3); HRFABMS calcd for C15H17BrN3O4m/z [M+H]+ 384.0382, 382.0402. found 384.0374, 382.0393.
Reaction SMILES: F[C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18]C)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:20])[CH:8]=2)=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[CH2:6]([C:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=2)[N:9]([CH3:20])[CH:8]=1)[C:5]1[CH:4]=[CH:3][CH:2]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc2c(Cc3ccc(F)cc3)cn(C)c2c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(Cc2ccccc2)c2ccc(C(=O)O)cc21
Yield: 104.1 %

Procedure:
A solution of compound 25c (175 mg, 0.59 mmol), and LiOH.H2O (101 mg, 2.41 mmol) in THF/H2O (3/3 mL) was stirred at room temperature for 6 h. The resultant mixture was concentrated and partitioned between CH2Cl2 and water. The aqueous layer was acidified with 1N HCl(aq) to pH˜4. The organic layer was dried over Na2SO4 and concentrated to give compound 25d (163 mg), which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([CH2:13][CH:14]=O)[CH2:9]1)=[O:7].[CH2:31]([O:33][CH2:34][CH2:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[N:45]1[CH2:51][CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)[CH3:32].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(OCC)(=O)C.CO.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:48]2[CH2:49][CH2:50][CH2:51][N:45]([C:37]3[N:36]([CH2:35][CH2:34][O:33][CH2:31][CH3:32])[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[N:38]=3)[CH2:46][CH2:47]2)([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CC=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CCOCCn1c(N2CCCN(CCC3(c4ccc(Cl)c(Cl)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 72 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-oxoethyl)pyrrolidine (0.51 g, 1.13 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.40 g, 1.36 mmol), and silica gel (about 2 g) in methanol (24 mL) and stir. After 3 days, add sodium cyanoborohydride (0.71 g, 11.3 mmol) and 3 Å molecular sieves (about 12 g) and stir under an inert atmosphere. After 18 hours, add a solution of 2 M sodium hydroxide and dichloromethane and stir. After 18 hours, filter, separate the layers in the filtrate, and extract the organic layer with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/methanol to give, after drying in vacuo at 82° C., the title compound: mp; 55-65° C. Rf=0.36 (silica gel, 1/1 ethyl acetate/methanol). Elemental Analysis calculated for C38H47C12N5O5: C, 62.98; H, 6.54; N, 9.66; Found: C, 62.65; H, 6.65; N,9.51.
Reaction SMILES: CS(O[C@H:6]1[CH2:9][C@@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)(=O)=O.C(OC(=O)N[C@H]1C[C@H](N)C1)(C)(C)C.[NH2:31][NH2:32]>C(O)C>[C:14]([O:13][C:11](=[O:12])[NH:10][C@H:8]1[CH2:9][C@H:6]([NH:31][NH2:32])[CH2:7]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](OS(C)(=O)=O)C1
Reactant: NN
Agent: CC(C)(C)OC(=O)N[C@H]1C[C@H](N)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](NN)C1
Temperature: 130 °C

Procedure:
Cis-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate (intermediate in the synthesis of tert-butyl(trans-3-aminocyclobutyl)carbamate from Radchenko, D. S., Pavlenko, S. O., et al J. Org. Chem. 2010, 75, 5941-5952, 10 g, 37.7 mmol) and hydrazine (anhydrous, 5 ml, 159 mmol) were added to ethanol (100 mL) and scaled in a pressure vessel. The mixture was heated at 130° C. for 1½ hours. The crude was evaporated to dryness under reduced pressure. Purification using silica chromatography (0-10% (2 N ammonia in methanol) in dichloromethane gradient, visualize with iodine chamber) gave the desired tert-butyl(trans-3-hydrazinylcyclobutyl)carbamate (4.1 g, 20.37 mmol, 54.0% yield).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][C:4]#[CH:5].Cl[C:8]([O:10][CH2:11][CH3:12])=[O:9]>>[CH2:11]([O:10][C:8](=[O:9])[C:5]#[C:4][CH2:3][CH:2]([CH3:6])[CH3:1])[CH3:12]
Reactant: C#CCC(C)C
Reactant: CCOC(=O)Cl
Product: CCOC(=O)C#CCC(C)C

Procedure:
The title compound was prepared from 4-methyl-pent-1-yne and ethyl chloroformate in accordance with the procedures of G. Cai et al., Tetrahedron, 2006, (5697-5708).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:6].CC(C)([O-])C.[K+]>O1CCCC1>[CH:8]1([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: O=C(NCCCl)NC1CCCc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1NCCN1C1CCCc2ccccc21
Reaction time: 8 h
Yield: 21.6 %

Procedure:
To a stirred solution of 3.8 grams (0.015 mole) of 1-(2-chloroethyl)-3-(1,2,3,4-tetrahydro-1-naphthyl)urea in 75 ml. dry tetrahydrofuran is added dropwise a solution of 2.25 grams (0.02 mole) of potassium tert-butoxide in 50 ml. of dry tetrahydrofuran under a nitrogen atmosphere. The reaction is then allowed to proceed at ambient temperature overnight. The mixture is then evaporated at reduced pressure. The residue is partitioned between water and ether. The ether layer is washed with water, dried, sodium sulfate, and evaporated at reduced pressure. Crystallization of the residue from acetone-ether-hexane gives 0.70 grams of product, melting point 134° to 139.5° C. Recrystallization from acetone-hexane gives the analytical sample, melting point 138° to 141.5° C. Analysis calculated for C13H16N2O: C, 72.19; H, 7.46; N, 12.95. Found: C, 72.04; H, 7.43; N, 12.89.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)Cl.CO.[BH4-].[Na+]>C1(C)C=CC=CC=1.CO>[CH2:17]([N:14]1[CH2:15][CH:16]=[C:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([Br:1])[CH:3]=2)[CH2:12][CH2:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1cc2c(c(-c3ccncc3)c1)OCC2
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Brc1cc2c(c(C3=CCN(Cc4ccccc4)CC3)c1)OCC2
Temperature: 0 °C
Yield: 71 %

Procedure:
To a solution of 4-(5-bromo-2,3-dihydro-benzofuran-7-yl)-pyridine in toluene was added benzyl bromide (1 eq.) and the reaction mixture was stirred under reflux for 14 h. Reaction was monitored by TLC (CH2Cl2/MeOH 95:5) and revealed total conversion to an intermediate. Complete evaporation of the solvent gave a white solid. The solid was dissolved in MeOH under argon and cooled down to 0° C., NaBH4 (2.05 eq.) was added portion-wise (exothermic reaction) and the reaction mixture was stirred for 3 h at RT. Evaporation of MeOH, redissolution in CH2Cl2 and sequential washing with 1N NaHCO3 and brine, followed by purification by SiO2 gel chromatography (CH2Cl2/MeOH: 98/2) gave 71% yield of the tide compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.CC([O-])(C)C.[K+].CS(O[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)[CH2:28][CH3:29])(=O)=O>C1COCC1.CCOC(C)=O>[C:36]([C:32]1[CH:31]=[C:30]([CH:27]([N:7]2[C:8]3[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[CH2:28][CH3:29])[CH:35]=[CH:34][CH:33]=1)#[N:37]
Reactant: CCC(OS(C)(=O)=O)c1cccc(C#N)c1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(c1cccc(C#N)c1)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
To a suspension of 4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.030 g, 0.143 mmol) in THF (5 mL) was added KOtBu (1M in THF) (0.157 mL, 0.157 mmol). After stirring at rt for a couple of min, a solution of 1-(3-cyanophenyl)propyl methanesulfonate (0.0512 g, 0.214 mmol) in THF (1 mL) was added, and the mixture was heated at 80° C. in a sealed tube. The reaction was monitored by LCMS. After ˜30 min, additional 1-(3-cyanophenyl)propyl methanesulfonate (0.0342 g, 0.143 mmol) in THF (1 mL) was added, and the mixture was heated at 80° C. for another 30 min. Upon cooling, the reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel using 0-25% EtOAc-hexane gradient. The material was further purified by preparative HPLC (Phenomenex Luna column; gradient: 10-100% MeCN-water with 0.1% TFA). The fractions with product were combined and concentrated down to the aqueous phase, which was then partitioned between EtOAc (25 mL) and saturated aq. NaHCO3 solution (20 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give 1-(1-(3-cyanophenyl)propyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.014 g, 26% yield): MS (ESI): m/z 354 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:10][C:11]([NH2:13])=[O:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.C(O)(=[O:16])C>O>[O:16]=[C:9]1[C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]([NH:10][C:11]([NH2:13])=[O:12])[CH2:7][CH2:8]1
Reactant: CC(=O)O
Reactant: NC(=O)NC1CCCc2sccc21
Solvent: O
Product: NC(=O)NC1CCC(=O)c2sccc21

Procedure:
A sample of 6 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea is dissolved in 375 ml. of 50% aqueous acetic acid and 75 grams of ceric ammonium nitrate is added in portions over a 10 minute period with stirring at 25° C. to 35° C. The pale-orange solution is stirred for another 5 minutes and 100 ml. of water is added. The solution is extracted twice with ethyl acetate (450 ml. and 350 ml.) and the combined extracts are washed with 100 ml. of water. The organic extract is evaporated to dryness in vacuo and the brown residue is crystallized from methanol to afford 2.37 grams of 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea, melting point 237° C. to 238° C. dec. Recrystallization from methanol affords purified product, melting point 245° C. to 246° C. dec.