Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].[BrH:10].N([O-])=O.[Na+]>O>[Br:10][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4]
Reactant: Br
Reactant: CCCC[C@H](N)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCCC[C@H](Br)C(=O)O
Reaction time: 2 h

Procedure:
(S)-2-aminohexanoic acid (FW 131.2, also known as L-norleucine) (1 g, 7.62 mmol), which is commercially available from Sigma Chemical Co at Sigmaaldrich.com, is dissolved in a mixture of HBr 48% (7.0 mL, 61 mmol) and H2O (10 mL). At 0° C., a solution of NaNO2 (1.7 g, 24 mmol) in H2O (5 mL) is added over a period of 30 min. The reaction is stirred for two hours. The reaction mixture is degassed in vacuo and extracted with EtOAc (2×20 mL). The extracts are washed with water (15 mL), dried (Na2SO4), filtered and evaporated to give (S)-2-bromohexanoic acid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].[OH:11][C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)cc(F)c1
Reactant: Oc1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)cc(Oc2cncnc2)c1
Yield: 48.5 %

Procedure:
3,5-Difluorobenzonitrile (1.0 g, 7.2 mmol, 1.0 eq), 5-hydroxypyrimidine (691 mg, 7.19 mmol, 1.00 eq), K2CO3 (1.2 g, 8.7 mmol, 1.2 eq) and DMF (17 mL) were added to a microwave vial and microwaved at 150° C. for 15 minutes. The reaction was filtered and concentrated on silica gel (5 g). The silica gel was loaded on top a fresh bed of silica gel and washed with 50% ethyl acetate/hexane. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 750 mg (48%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.75 (s, 2H), 7.71 (ddd, J=8.4, 2.2, 1.2 Hz, 1H), 7.62-7.61 (m, 1H), 7.56 (dt, J=10.0, 2.3 Hz, 1H); [M+1]+: 216.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17](=[O:28])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29](Cl)(=[O:31])[CH3:30].O>C1COCC1>[C:29]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][C:17](=[O:28])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CCOc1ccccc1NC(=O)OCCN1CCN(c2cccc(N)c2)CC1
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccccc1NC(=O)OCCN1CCN(c2cccc(NC(C)=O)c2)CC1
Reaction time: 20 h
Yield: 42.2 %

Procedure:
To a mixture of 77 mg (0.2 mmol) of 2-[4-(3-aminophenyl)piperazino]ethyl-N-(2-ethoxyphenyl)carbamate derivative and 44.6 μl (0.32 mmol, 1.6 eq) of TEA in 5 ml of THF, 71 μl (0.3 mmol, 1.5 eq) of acetyl chloride is added. Shaking is carried out at room temperature for about 20 hours. Then H2O is added and the aqueous phase is extracted with CH2Cl2. After drying on Na2SO4 and concentration under vacuum, a white solid is obtained which is purified by column chromatography (eluent CH2Cl2/iPrOH 9:1) to produce 36 mg of the expected product as a brown oil (yield: 43%).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]1[O:16][C@H:15]1[CH2:17]Cl>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:17][C@@H:15]3[CH2:14][O:16]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClC[C@H]1CO1
Reactant: Oc1ccc(C2CCCCC2)cc1
Product: c1cc(C2CCCCC2)ccc1OC[C@@H]1CO1

Procedure:
The title compound was prepared from 4-cyclohexyl-phenol and R-epichlorohydrin employing the procedures as set forth in Step 1 of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:17](OC)(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[SH:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]3[S:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[C:17](=[O:25])[N:16]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccccc1S
Reactant: COc1ccc(-c2cccc(C#N)n2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccc(-c3nc(=O)c4ccccc4s3)n2)cc1
Yield: 66.1 %

Procedure:
6-(4-Methoxyphenyl)-2-pyridinecarbonitrile (0.81 g, 3.8 mmol) and methyl thiosalicylate (1.07 g, 6.3 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 8 hrs. After cooling, the precipitates were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (0.87 g, 65%) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]([SH:15])[CH2:13][SH:14])[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[OH:9].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:27][CH3:28])[C:25]=1[OH:26])[CH:21]=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:28][O:27][C:24]1[CH:23]=[C:20]([C@H:21]2[S:15][C@H:12]([C:5]3[CH:6]=[C:7]([O:10][CH3:11])[C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][S:14]2)[CH:19]=[C:18]([O:17][CH3:16])[C:25]=1[OH:26]
Reactant: COc1cc(C(S)CS)cc(OC)c1O
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1cc([C@@H]2SC[C@@H](c3cc(OC)c(O)c(OC)c3)S2)cc(OC)c1O

Procedure:
1-(3,5-dimethoxy-4-hydroxyphenyl-1,2-ethanedithiol (40) (2.46 g, 10.0 mmole), 3,5-dimethoxy-4-hydroxybenzaldehyde (indicated as arylaldehyde E in FIG. 1) (1.32 g, 7.20 mmole) and 1.00 g of pyridinium paratoluene sulfonate are added to 50 ml dry benzene and refluxed with Dean-Stark removal of the benzene-water azeotrope overnight. The benzene is removed in vacuo, and the remaining oil redissolved in dichloromethane. The organic layer is washed with 10% NaHCO3 and H2O. The organic layer is dried over MgSO4, filtered, and evaporated in vacuo to a white solid which is recrystallized from methanol (2.510 g, 85%). The trans isomer (0.683 g) is isolated by recrystallization from methanol. NMR: (CDCl3) 3.45,dd,1H;3.61,dd,1H; 3.91,s,6H;3.92,s,6H;5.07,dd,1H;5.50,d,2H;5.83,s,1H; 6.73,s,2H;6.84,s,2H. M.S.: (CI) 411 (100%). Melting Point: 169°-170° C. C,H,S Analysis: (theoretical, actual) C (55.59,55.58); H (5.40,5.44); S (15.62,15.56).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[C:31]([C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1)#[N:32]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([C:31]#[N:32])[CH:34]=4)=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: N#Cc1cccc(N=C=O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(=O)Nc2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 30.8 mg (0.21 mmol) of 3-cyanophenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 32 mg (62.1% of theory) of the title compound are obtained.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C1(C)C=CC=CC=1.[CH2:14]([O:25][C:26]1C=[CH:33][CH:32]=[CH:31][C:27]=1C(O)=O)[CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CN(C=O)C.C(Cl)Cl>[CH2:14]([O:25][C:26]1[CH:27]=[CH:31][CH:32]=[CH:33][C:1]=1[C:2]([Cl:4])=[O:3])[CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC/C=C\CCCOc1ccccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCC/C=C\CCCOc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
800 μL of oxalyl chloride (9.17 mmol) and two drops of anhydrous DMF are added under argon to 76 mg of toluene-dried acid 30 (262 μmol) dissolved in 15 mL of anhydrous DCM. The medium is stirred at room temperature for two hours and then concentrated to give 80 mg of a yellow oil, i.e. a yield of 99%.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17](OC)[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][N:5]=1)C.B(Br)(Br)Br.[C:25]([O-])(O)=[O:26].[Na+]>ClCCl>[CH3:25][O:26][C:16]1[CH:17]=[CH:18][C:12]2[S:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([NH:3][CH3:1])=[N:5][CH:6]=3)=[N:14][C:13]=2[CH:15]=1
Reactant: CCNc1ccc(-c2nc3ccc(OC)cc3s2)cn1
Reactant: O=C([O-])O
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: CNc1ccc(-c2nc3cc(OC)ccc3s2)cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To N-ethyl-5-(6-methoxy-1,3-benzothiazol-2-yl)pyridin-2-amine (52.8 mg, 0.185 mmol) in dichloromethane (2 mL) was added BBr3 in dichloromethane (1 M, 925 μL) at 0° C. under an argon atmosphere. The reaction was then stirred at 0° C. for 3 h before it was neutralized with NaHCO3 (sat aq). The precipitated product was filtered off, washed with water and DCM and dried. Recrystallization from (MeOH/toluene) gave the title compound (11 mg) as a white solid. 1H NMR δ ppm 9.75 (br s, 1H) 8.58 (d, 1H) 7.93 (dd, 1H) 7.73 (d, 1H) 7.34 (d, 1H) 7.19 (t, 1H) 6.92 (dd, 1H) 6.56 (d, 1H) 3.32-3.38 (m, 2H) 1.16 (t, 3H); MS m/z (M+H) 272.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH:8]2[CH2:10][CH2:9]2)[N:6]=1.[CH:11]1[C:24]2[CH:23]([C:25](Cl)=[O:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:16][C:15]=2[CH:14]=[CH:13][CH:12]=1>>[CH:8]1([CH2:7][N:5]2[N:4]=[N:3][C:2]([NH:1][C:25]([CH:23]3[C:24]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[O:16][C:17]4[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:26])=[N:6]2)[CH2:10][CH2:9]1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: Nc1nnn(CC2CC2)n1
Product: O=C(Nc1nnn(CC2CC2)n1)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p. 222-224° C. and MS: (neg. ions): m/e=346.2 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-cyclopropylmethyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:18]=1)=[N:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[CH:9][N:10]=2.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20].Cl.[OH-].[K+]>N1C=CC=CC=1.O>[CH2:19]([NH:21][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:18]=1)=[N:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[CH:9][N:10]=2)=[O:23])[CH3:20]
Reactant: CCN=C=O
Reactant: Nc1ccc2ncc(-c3ccc(O)cc3)nc2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CCNC(=O)Nc1ccc2ncc(-c3ccc(O)cc3)nc2n1
Temperature: 75 °C

Procedure:
0.50 g of 4-(6-aminopyrido[2,3-b]pyrazin-3-yl)phenol (2.10 mmol) were initially charged in 5.0 ml of pyridine. 183 μl of ethyl isocyanate (2.31 mmol) were added dropwise at room temperature and the mixture was heated to 70-80° C. for 2 h. Thereafter, another 183 μl of ethyl isocyanate were added and the mixture was heated to 70-80° C. for a further 2 h. Once the reaction had ended, the reaction mixture was added to ice-water and neutralized with 1N hydrochloric acid. The precipitated product was filtered off with suction and dried. The product which had been filtered was partly dissolved in ethanol and admixed with 52 mg of potassium hydroxide (0.93 mmol), dissolved in water. The mixture was heated to 40° C. for approx. 1 h. Thereafter, the reaction solution was neutralized with 1N hydrochloric acid and the solvent was removed under reduced pressure. The resulting solid was purified by column chromatography on silica gel (dichloromethane/methanol eluent). This gave a yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Cl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:20][C:19]4[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: Fc1cccc(CCl)c1
Reactant: Sc1nnc(-c2ccc3occc3c2)o1
Product: Fc1cccc(CSc2nnc(-c3ccc4occc4c3)o2)c1
Yield: 84 %

Procedure:
In the same manner as in Example 1 and using 5-(1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-fluorobenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 84%) was obtained as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1.I[CH2:19][CH2:20][CH2:21][CH3:22]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:17][CH2:19][CH2:20][CH2:21][CH3:22])[C:6]([CH3:15])([CH3:16])[CH2:7][CH:8]=[C:9]2[CH:12]([CH3:13])[CH3:14]
Reactant: CCCCI
Reactant: CC(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Product: CCCCOc1cc2c(cc1Br)C(C(C)C)=CCC2(C)C
Yield: 66 %

Procedure:
Following General Procedure O, 3-bromo-5-isopropyl-8,8-dimethyl-7,8-dihydronaphthalen-2-ol (Compound 97, 0.36 g, 1.2 mmol) was reacted with 1-iodobutane to afford 0.28 g (66%) of the title compound as a clear oil.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([OH:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH3:24])[CH2:4][CH3:5])[CH3:2].[H-].[Na+].[CH3:27]I>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([O:22][CH3:27])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH3:24])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(O)cc2C)c1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(OC)cc2C)c1C
Reaction time: 0.08 h

Procedure:
To a solution of 4-[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenol (40 mg, 0.12 mmol) in 3 ml of dry THF was added 10 mg of 60% sodium hydride in oil at room temperature. After stirring for 5 min, 0.3 ml of methyl iodide was added and the resulting mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a yellow solid. The solid was purified through silica gel column chromatography using hexane to 1:1 chloroform:hexane as eluent to yield 20 mg of the title compound as yellow solid. 1H NMR (CDCl3) δ 6.66 (s, 2H), 6.28 (s, 1H), 4.20 (m, 1H), 3.79 (s, 3H), 2.20 (s, 3H), 2.19 (s, 3H0, 2.08 (s, 6H), 1.71 (m, 4H), 0.97 (t, 6H) ppm.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-:18].[Na+].[Na+].Cl.S(=O)(O)[O-].[Na+]>[Mn]([O-])(=O)(=O)=O.[K+]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:10]([OH:18])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: O=S([O-])O
Product: COc1ccc(C(=O)O)cc1OC1CCCC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A stirred saturated aqueous solution of potassium permanganate (100 mL) is treated with 3-cyclopentyloxy-4-methoxybenzaldehyde (7.4 g; that is prepared as described hereinbefore in Reference Example 1) and sodium carbonate (3.4 g) and the mixture is stirred at 50° C. for 1 hour, and then cooled to room temperature. The reaction mixture is acidified by treatment with concentrated hydrochloric acid and then it is treated with aqueous sodium bisulfite solution until a colorless solution is obtained. The reaction mixture is extracted with dichloromethane (2×100 mL) and the organic extracts are dried over magnesium sulfate and concentrated. The resulting residue is recrystallized from diethyl ether, to give 3-cyclopentyloxy-4-methoxybenzoic acid (4.78 g) in the form of white crystals. [NMR(CDCl3): 1.7(s,2H),1.8-2.2 (m,6H),3.95(s,3H),4.85(s,1H),6.9(bs,1H)7.6(bs,1H), 7.8(s,1H),9.8(s,1H); Elemental analysis: C,65.6; H,6.8%; Calculated: C,66.1; H,6.8%].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=4)[CH2:15][C:14](=[O:24])[CH2:13][CH:12]3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N-:32]=[N+]=[N-].[Na+]>C(#N)C.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@:6]3([C@@H:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=4)[CH2:15][C:14](=[O:24])[NH:32][CH2:13][C@H:12]3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(C2CC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: Cc1cccc([C@H]2CC(=O)NC[C@@H](c3cccc(Cl)c3)[C@]23C(=O)Nc2cc(Cl)ccc23)c1
Yield: 7.8 %

Procedure:
In a manner similar to the method described in example 2 (method A), rac-(1R,2S,6R)-6′-chloro-2-(3-chlorophenyl)-6-(3-methylphenyl)spiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (140 mg, 0.31 mmol) was reacted with NaN3 (50.1 mg, 0.78 mmole) in the presence of TiCl4 (1.0 M in CH2Cl2, 0.31 mL) (Aldrich) in acetonitrile (10 mL) followed by chiral chromatograph to give (3S,4R,5R)-6′-chloro-3-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-5-(3-methylphenyl)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (11.2 mg): HRMS (ES+) m/z Calcd for C26H22Cl2N2O2+H [(M+H)+]: 465.1131. Found: 465.1132; (3S,4R,5R)-6′-chloro-5-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3-(3-methylphenyl)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (10.7 mg): HRMS (ES+) m/z Calcd for C26H22Cl2N2O2+H [(M+H)+]: 465.1131. Found: 465.1131; (3R,4S,5S)-6′-chloro-3-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-5-(3-methylphenyl)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (10.3 mg): HRMS (ES+) m/z Calcd for C26H22Cl2N2O2+H [(M+H)+]: 465.1131. Found: 465.1131; and (3R,4S,5S)-6′-chloro-5-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3-(3-methylphenyl)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (10.1 mg): HRMS (ES+) m/z Calcd for C26H22Cl2N2O2+H [(M+H)+]: 465.1131. Found: 465.1131.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].[OH-].[Na+].[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[OH:20])[CH:15]=O>C(O)C>[OH:11][C:12]1[CH:13]=[C:14]([CH:15]=[N:2][N:3]2[CH2:7][CH2:6][NH:5][C:4]2=[O:8])[CH:17]=[CH:18][C:19]=1[OH:20]
Reactant: NN1CCNC1=O
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1NCCN1N=Cc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 61.4 g (0.446 mol) of 1-amino-2-imidazolidinone hydrochloride in 300 ml of 80% aqueous ethanol were added 223 ml of 2N sodium hydroxide (0.446 mol) and a solution of 61.6 g (0.446 mol) of 3,4-dihydroxybenzaldehyde in 300 ml of 80% aqueous ethanol. The mixture was stirred for 20 minutes at room temperature, and the precipitate filtered off by suction, washed with ethanol and dried in vacuo (yield: 34.5 g; melting point 257° C., dec).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])[CH2:15][CH2:14]3)(=[O:10])=[O:9])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>C1COCC1.CCOC(C)=O>[CH:22]1([C:20]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([S:8]([N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:34](=[O:37])[CH:35]=[CH2:36])[CH2:3][CH2:4]4)(=[O:10])=[O:9])=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[O:21])[CH2:23][CH2:24]1
Reactant: NC1CCN(S(=O)(=O)c2ccc3c(c2)CCN3C(=O)C2CC2)CC1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc3c(c2)CCN3C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
[5-(4-Amino-piperidine-1-sulfonyl)-2,3-dihydro-indol-1-yl]-cyclopropyl-methanone (0.09 g, 0.25 mmol) was dissolved in THF (5 ml). To this was added diisopropylethylamine (0.2 ml, 1.0 mmol) in one portion followed by the drop wise addition of acryloyl chloride (0.02 ml, 0.27 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with EtOAc (50 ml) and washed sequentially with HCl (1M solution, 20 ml), NaOH (1M solution, 20 ml) and brine (20 ml), the organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 100% EtOAc) to give the title compound (0.035 g, 35% yield) as a white powder.
Reaction SMILES: O.O.[Sn](Cl)Cl.[Br:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:8]=1[NH2:9].[OH-].[Na+]>Cl>[NH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:7]([Br:6])[C:8]=1[NH2:9]
Reactant: Nc1c(Br)cccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1cccc(Br)c1N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirring slurry of tin(II) chloride dihydrate (8.28 g, 37 mmol) in conc. hydrochloric acid (40 mL) was added 2-bromo-6-nitroaniline (prepared as described in WO 02/22600, 1.99 g, 9.2 mmol), and the resulting mixture was stirred at room temperature for 5 min—an exotherm was observed. The mixture was stirred at reflux for 30 min, then allowed to cool to room temperature. The resulting slurry was poured onto crushed ice (˜100 mL), and the pH was adjusted to 14 by addition of sodium hydroxide pellets. The mixture was washed with diethyl ether (5×100 μL), then the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified on a Biotage SP1 apparatus, using a 2%–20% ethyl acetate in dichloromethane eluant system on a 25M silica column, yielding 1,2-diamino-3-bromobenzene as a brown oil, which solidified upon standing (1.50 g, 87%) m/z (ES+) 187, 189 [MH]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:3][CH2:2]1.[CH3:20][C:21]([CH3:29])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[NH2:22]>>[CH3:20][C:21]([NH:22][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[N:8]=1)=[O:19])([C:23]1[N:27]=[C:26]([CH3:28])[O:25][N:24]=1)[CH3:29]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CC3)c(OCC3CCCO3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=387.0 [M+H]+.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[N:16]=[C:15]([Cl:17])[CH:14]=[C:13]([C:18](OC)=[O:19])[N:12]=1>C1COCC1>[Cl:10][C:11]1[N:16]=[C:15]([Cl:17])[CH:14]=[C:13]([C:18]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:19])[N:12]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OC1CCCCC1)c1cc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A cold (0° C.) solution of cyclohexanol (3.82 ml; 36.2 mmol) was treated with sodium hydride (869 mg; 36.2 mmol) in dry THF (100 ml) and stirred for 30 min at 0° C. It was slowly added to a cooled (0° C.) solution of methyl 2,4-dichloropyrimidine-6-carboxylate (Apollo, 10.00 g; 48.3 mmol) in dry THF (200 ml) and the resulting mixture was stirred for 24 h. The reaction mixture was concentrated under vacuum. The residue was taken up in EtOAc and the organic layer was washed with water, then brine, dried over MgSO4, filtered off and concentrated under vacuum to afford a crude which was purified by flash chromatography eluting with cHex-EtOAc 8:2 to afford the title compound as a white solid.