Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH:4]1[CH:8]([CH:9]([CH2:11][CH2:12][CH3:13])[CH3:10])[S:7][CH2:6][CH:5]1O)([O-:3])=[O:2].S(Cl)(C)(=O)=O.C(N(CC)CC)C.O>ClCCl>[N+:1]([C:4]1[CH:8]([CH:9]([CH2:11][CH2:12][CH3:13])[CH3:10])[S:7][CH2:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCC(C)C1SCC(O)C1[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCC(C)C1SCC=C1[N+](=O)[O-]
Reaction time: 3.5 h
Yield: 56.7 %

Procedure:
After dissolving 150 mg of 4-nitro-5-(pentan-2-yl)tetrahydrothiophen-3-ol in 4 ml of dichloromethane, 86 mg of mesyl chloride and 138 mg of triethylamine were gradually dropped thereto at 4° C. The temperature of the solution was allowed to rise to room temperature, and the solution was stirred for 3.5 hours. Water was added to stop the reaction, and the solution was extracted with dichloromethane. The organic layer was dried with magnesium sulfate and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=10/1), thereby obtaining 78 mg of 3-nitro-2-(pentan-2-yl)-2,5-dihydrothiophene (yield: 57.3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)C=O)=[CH:4][CH:3]=1.C1(P(=[CH:43][CH:44]=[O:45])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:46]1C=CC=CC=1>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)[CH:46]=[CH:43][CH:44]=[O:45])=[CH:22][CH:21]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Reactant: c1ccccc1
Product: O=CC=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
The reaction was carried out following the general procedure described in Example 7. A suspension of 224.4 mg (0.72 mmole) of 3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-1-yl)-2-propenal and 220 mg (0.72 mmole) of triphenylphosphoranylidene acetaldehyde in 38 mL of dry benzene was stirred at room temperature for 16 hours. The crude reaction mixture was chromatographed on a silica gel column and the purified product thereby obtained was recrystallized from ethyl acetate-hexanes to give 194 mg (92%) of the title compound; m.p.=152.2°-153.7° C.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[CH:12]([C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:27])[CH2:20][C:21]([CH3:26])([CH3:25])[O:22]2)=[C:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]=1[C:34](=[O:46])[C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=1)([CH3:14])[CH3:13].CO>O1CCCC1>[OH:27][C@@H:19]1[C:18]2[C:23](=[CH:24][C:15]([CH:12]([CH3:13])[CH3:14])=[C:16]([C:34]([C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:43])[F:44])=[CH:37][CH:36]=3)=[O:46])[C:17]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:22][C:21]([CH3:25])([CH3:26])[CH2:20]1
Reactant: CC(C)c1cc2c(c(-c3ccccc3)c1C(=O)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccccc3)c1C(=O)c1ccc(OC(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
72 μl (410 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 2.3 mg (20 μmol) of (1R,2S)-1-aminoindan-2-ol in 1.5 ml of tetrahydrofuran, and the mixture is stirred for 30 min. The mixture is then cooled to 0° C., and a solution of 49 mg (100 μmol) of 7-isopropyl-2,2-dimethyl-5-phenyl-6-[4-(trifluoromethoxy)benzoyl]-2,3-dihydro-4H-chromen-4-one (Example 32A) in 3.5 ml of tetrahydrofuran is slowly added dropwise. The mixture is allowed to thaw slowly and stirred at room temperature overnight. Methanol is then added, and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative HPLC (method 1) gives the target product.
Reaction SMILES: C([Li])CCC.CCCCCC.[Si:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[F:42])[S:25]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Si:43]([O:50][CH2:51][CH2:52][CH2:53][CH2:54]I)([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]>O.O1CCCC1>[Si:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[F:42])([CH2:54][CH2:53][CH2:52][CH2:51][O:50][Si:43]([C:46]([CH3:47])([CH3:49])[CH3:48])([CH3:44])[CH3:45])[S:25]([C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)(=[O:27])=[O:26])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCCI
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCC(CCCCO[Si](C)(C)C(C)(C)C)(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexane solution, 0.358 ml, 0.562 mmol) was added to a tetrahydrofuran (4 ml) solution of the 2-[5-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]pentyl]-1,4-difluorobenzene (250 mg, 0.511 mmol) obtained in Example 15. The temperature of the resulting mixture was raised to room temperature. After cooling to −78° C., 4-(t-butyldimethylsilyloxy)-1-iodobutane (0.146 ml, 0.562 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extracts were combined, washed successively with water and brine, dried over MgSO4, and then concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (6% ethyl acetate-hexane), whereby the title compound (167 mg, 48%) was obtained as a colorless solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:19][CH2:20][NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.O>[C:13]([C:14]([CH3:16])([CH3:15])[CH2:19][CH2:20][NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[N:17]
Reactant: O=C(NCCBr)OCc1ccccc1
Reactant: CC(C)C#N
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C#N)CCNC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 21.1 %

Procedure:
Treat a −78° C. solution of diisopropylamine (35 g, 0.346 mol) in THF (300 mL), under N2, dropwise with a solution of n-butyllithium (2.5 M, 127 mL, 0.317 mol), warm to −30° C. for 0.5 h, re-cool to −78° C. and treat dropwise with a solution of isobutyronitrile (19.9 g, 0.288 mol) in THF (100 mL). Stir the mixture at −78° C. for 0.5 h, treat with a solution of benzyl (2-bromoethyl)carbamate (74 g, 0.288 mol) in THF (100 mL), stir at −78° C. for 1 h, then warm to RT and stir overnight. Treat the mixture with H2O, separate the layers, extract the aqueous layer with EtOAc, wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Petroleum ether) to afford the title compound (15 g, 21% yield). MS (m/z): 247.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].[Br:18][C:19]1[C:20]([O:29][CH3:30])=[C:21]([C:25]([O:27][CH3:28])=[O:26])[S:22][C:23]=1Br>C1(C)C=CC=CC=1>[Br:18][C:19]1[C:20]([O:29][CH3:30])=[C:21]([C:25]([O:27][CH3:28])=[O:26])[S:22][C:23]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: COC(=O)c1sc(Br)c(Br)c1OC
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2ccc(Cl)cc2Cl)c(Br)c1OC
Temperature: 110 °C
Yield: 47.1 %

Procedure:
16.60 g of (2,4-dichlorophenyl)boronic acid and then, dropwise, 87 ml of a 2M solution of Na2CO3 are added to a solution of 28.70 g of the compound of step A) in 110 ml of toluene. Argon is sparged into the reaction mixture for 30 minutes, 5.03 g of tetrakis are then added and the mixture is heated at 110° C. for 18 hours. After cooling to AT, 80 ml of distilled water are added to the reaction mixture, extraction is carried out with 80 ml of EtOAc, drying is carried out over Na2SO4 and the solvent is evaporated off under vacuum. The reaction crude is purified by silica gel chromatography, elution being carried out with heptane and then with a heptane/EtOAc mixture (85/15; v/v). 16.21 g of the expected compound are obtained.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:23]=[CH:22][N:13]([C@@H:14]2[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]2)[C:12](=[O:24])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:31](Cl)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CO>C(Cl)Cl>[C:31]([O:20][CH2:19][C@H:18]1[O:21][C@@H:14]([N:13]2[CH:22]=[CH:23][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:11][C:12]2=[O:24])[CH2:15][C@@H:16]1[OH:17])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1)c1ccccc1
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)n1)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
3.31 g (10 mmol) of N-benzoyl-2'-deoxycytidine were added to 25 ml of pyridine, and then 3.07 g (11 mmol) of trityl chloride were added to the suspension. The resulting suspension was stirred at 100° C. for 1 hour, after which it was allowed to cool to room temperature. The pyridine was then removed by distillation under reduced pressure. The resulting residue was dissolved in a mixture of ethyl acetate and a saturated aqueous solution of sodium chloride. The organic layer was separated and washed twice, each time with a saturated aqueous solution of sodium chloride. The solution was then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel (Lober column Si-60, Size C) using a gradient elution method, with mixtures of methanol and methylene chloride ranging from 2:98 to 5:95 by volume as the eluent, to give 1.47 g (yield 26%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]#[N:9])[C:3]=1[C:10]#[N:11].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:10]#[N:11])=[C:4]([CH2:7][C:8]#[N:9])[N:5]([CH2:19][C:20]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)=[O:21])[N:6]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: N#CCc1n[nH]c(N)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#CCc1c(C#N)c(N)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 5-amino-3-cyanomethyl-1H-pyrazole-4-carbonitrile, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=3/2) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 6.96–7.2 (m, 2H), 6.86–6.92 (m, 2H), 5.2 (s, 2H), 4.86 (s, 2H), 3.78–3.86 (m, 4H), 3.7 (s, 2H), 3.08–3.16 (m, 4H). MS (ES) M+H expected 367.39, found 368.1.
Reaction SMILES: C(N[C:5](=[CH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([Cl:18])=[C:13]([CH3:19])[CH:12]=1)[C:6]([O:8]C)=[O:7])(=O)C.Cl.[OH2:21]>CN1CCCC1=O>[Cl:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([CH2:10][C:5](=[O:21])[C:6]([OH:8])=[O:7])=[CH:12][C:13]=1[CH3:19]
Reactant: COC(=O)C(=Cc1cc(C)c(Cl)c(C)c1)NC(C)=O
Reactant: O
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1cc(CC(=O)C(=O)O)cc(C)c1Cl
Reaction time: 6 h

Procedure:
29.4 g (105 mmol) methyl 2-acetylamino-3-(4-chloro-3,5-dimethylphenyl)-acrylate in 330 mL N-methyl-2-pyrrolidinone were combined with 500 mL cooled 4 M HCl, stirred for 6 h at reflux temperature and for 16 h at RT. After the reaction had ended the reaction mixture was poured onto 1650 mL water, stirred for 1 h, suction filtered and the crystals were dried at 50° C. in the vacuum drying cupboard. The product was recrystallised from toluene.
Reaction SMILES: N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4N=NC(CC)=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.[ClH:45].[C:46]1([CH:52]([C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70](NCC4C=CC=CN=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[NH2:100][CH2:101][C:102]1[CH:103]=[C:104]([OH:108])[CH:105]=[CH:106][CH:107]=1>>[ClH:45].[C:94]1([CH:52]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70]([NH:100][CH2:101][C:102]4[CH:107]=[CH:106][CH:105]=[C:104]([OH:108])[CH:103]=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1
Reactant: NCc1cccc(O)c1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6cccc(O)c6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethyl pyridine with 3-aminomethyl-phenol. MS (ES+) m/e 745.47 (MH+).
Reaction SMILES: [C:1]1([N:7]2[C:12](=O)C3SC=C(C4C=CC=CC=4)C=3N=C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)OCC.[Cl:50]C1C=CC(N)=CC=1>C(O)(=O)C>[Cl:50][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:36](=[O:38])[C:25]3[S:26][CH:27]=[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[C:24]=3[N:23]=[CH:12]2)=[CH:2][CH:3]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)c1scc(-c2ccccc2C)c1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: Cc1ccccc1-c1csc2c(=O)n(-c3ccc(Cl)cc3)cnc12
Yield: 28.4 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(o -tolyl)thiophene-2-carboxylate (80 mg, 0.32 mmol), triethyl orthoformate (0.7 ml), 4-chloroaniline (76.8 mg, 0.6 mmol), and acetic acid (0.1 ml) were used to give 33.5 mg (0.09 mmol, 28.4% yield) of the title compound.
Reaction SMILES: S(O[CH2:12][C:13]12[CH2:27][CH:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=31)[C:19]1[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=1)(C1C=CC(C)=CC=1)(=O)=O.[O-][C:29]#[N:30].[K+]>CN(C)C=O.O>[CH:15]1[C:14]2[C:13]3([CH2:12][C:29]#[N:30])[CH2:27][CH:20]([C:21]4[C:26]3=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)OCC23CC(c4ccccc42)c2ccccc23)cc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC12CC(c3ccccc31)c1ccccc12
Temperature: 150 °C

Procedure:
A mixture of 9-tosyloxymethyl-9,10-dihydro-9,10-methanoanthracene (188 mg) and potassium cyanate (40 mg) in dimethylformamide (2 ml) was heated at 150° C. for 7 hours. The reaction mixture was diluted with water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give crude crystals of (9,10-dihydro-9,10-methano-9-anthryl)acetonitrile, which was recrystallized from isopropanol to give pure crystals. M.P. 130°-131° C.
Reaction SMILES: C[O:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([O-:7])=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[CH:12]1([NH:15][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[OH:2])[CH2:14][CH2:13]1
Reactant: COc1ccccc1C(=O)[O-]
Reactant: NC1CC1
Solvent: Cc1ccccc1
Product: O=C(NC1CC1)c1ccccc1O
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A mixture of methylsalicylate (4.36 g, 28.69 mmol) and cyclopropylamine (1.64 g, 28.69 mmol) was heated at 80–100° C. for 3 h. An additional 0.5 equivalent of cyclopropylamine was added and the reaction mixture was kept at 70° C. for overnight. The reaction mixture was co-evaporated with toluene and the residue was purified by silica gel flash chromatography to give the subtitle compound (2.71 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][C:24]=1[O:32][CH3:33].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][C:24]=4[O:32][CH3:33])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 84.7 %

Procedure:
A stirred of mixture of 6-fluoro-3-(4-piperidinyl)-1H-indazole (1.9 g, 0.0086 mol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone 2.6 g, 0.0086 mol), K2CO3 (1.2 g), and acetonitrile (7.5 ml) was refluxed for 6 hr. The reaction was poured into water and a white solid settled from solution. This was collected, dried and afforded 3.2 g of product. The product was recrystallized from ethanol to yield 2.7 g (71%) of 1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]butoxy-3-methoxyphenyl]ethanone as glistening white flakes, m.p.=158°-160° C.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:14][CH:15]=1
Reactant: O=C1NCc2ccccc21
Reactant: Fc1ccc(CBr)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1Cc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.133 g, 1 mmol), 1-bromomethyl-4-fluoro-benzene (0.227 g, 1.2 mmol), Cs2CO3 (0.816 g, 2.5 mmol), and 18-crown-6 (0.026 g, 0.1 mmol) in acetone (5 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(4-fluoro-benzyl)-2,3-dihydro-isoindol-1-one (0.198 g, 82%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.26 (s, 2H), 4.68 (s, 2H), 7.04 (t, 2H), 7.35-7.54 (m, 5H), 7.90 (d, 1H). GC-MS: m/z 241 (M)+
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1.[CH3:22][C:23]1[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=1>>[CH3:22][C:23]1[CH:27]=[C:26]([CH3:28])[N:25]([C:2]2[N:11]=[C:10]([NH:21][C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:24]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: COc1cccc(N)c1
Reactant: Cc1cc(C)[nH]n1
Product: COc1cccc(Nc2nc(-n3nc(C)cc3C)nc3ccccc23)c1

Procedure:
Was prepared according to Method B from 2,4-dichloroquinazoline, m-anisidine and 3,5-dimethylpyrazole. Mp. 193.1-194.7° C.
Reaction SMILES: C#C.[CH2:3]([N:10]1[CH2:15][CH2:14][O:13][CH:12]([CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I-:28].[Li+]>>[CH2:3]([N:10]1[CH2:15][CH2:14][O:13][CH:12]([CH2:16][I:28])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Agent: C#C
Agent: [Li+]
Product: ICC1CN(Cc2ccccc2)CCO1

Procedure:
The starting material for use in processes (a), (b) and (h) in which A is a vinylene radical may be prepared, as described in Example 1, by reaction of 4-benzyl-2-(toluene-p-sulphonyloxymethyl)morpholine and lithium iodide to give 4-benzyl-2-iodomethylmorpholine. This compound is then reacted with triphenyl phosphine to give 4-benzylmorpholine-2-ylmethyl triphenyl phosphonium iodide which is subsequently reacted with a base to form the corresponding phosphorane. This intermediate is reacted in situ with the appropriate substituted benzaldehyde to give 4-benzyl-2-(β-substituted phenylvinyl)morpholine as a mixture of cis and trans isomers. These isomers are, if necessary, separated by chromatography, or by fractional crystallisation of an acid-addition salt, and if required this N-benzyl derivative is used to form other N-substituted starting materials. Thus reaction with an aryl or optionally substituted alkyl chloroformate gives the corresponding phenoxy- or alkoxy-carbonyl derivative, or reaction with cyanogen bromide gives the corresponding N-cyano derivative.
Reaction SMILES: C([N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][C:15]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:14]=3[CH2:13]2)[CH2:8][CH2:7]1)(OCC)=O.C(O)CO.[OH-].[K+]>O>[Cl:27][C:25]1[CH:24]=[CH:23][C:15]2[S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:12]([N:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)[CH2:13][C:14]=2[CH:26]=1
Reactant: CCOC(=O)N1CCN(C2Cc3cc(Cl)ccc3Sc3ccccc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Clc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2

Procedure:
110 g of 1-carbethoxy-4-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine, 1.5 litres of ethylene glycol, 104 g of potassium hydroxide and 5.4 ml of water are heated to 160° C for 1 hour. The mixture is then poured on to water and extracted with chloroform. The organic phase is washed with water, dried over magnesium sulphate and evaporated. There is obtained 1-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[Cl:16]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:11]([Cl:16])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1c(N)ccc2ccccc12
Solvent: CC#N
Product: COC(=O)c1c(N)c(Cl)cc2ccccc12
Temperature: 60 °C
Reaction time: 7 h
Yield: 32.9 %

Procedure:
A mixture of methyl 2-amino-1-naphthoate (0.7 g, 3.48 mmol) in acetonitrile (15 mL) was treated with N-chlorosuccinimide (490 mg, 3.65 mmol), stirred at 60° C. for 7 hours, cooled to room temperature, stirred overnight, concentrated, and purified by flash column chromatography on silica gel with 10% ethyl acetate/n-hexane to provide the desired product (270 mg). MS (ESI(−)) m/e 234 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.13 (s, 1H), 8.10 (d, 1H), 7.75 (d, 1H), 7.46 (dt, 1H), 7.26 (dt, 1H), 6.62 (s, 2H), 3.95 (s, 3H).