Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[C:19]([F:24])[CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:25][C@@H:26]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[NH:27]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:27]4[C@H:26]([CH3:25])[CH2:30][CH2:29][S:28]4(=[O:32])=[O:31])=[C:19]([F:24])[CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)c(F)c3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)c(F)c3)CC2)c(C)c1
Yield: 8.4 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](3-fluoro-4-iodophenyl)methanone (600 mg) described in Preparation Example 159 and (R)-3-methylisothiazolidine 1,1-dioxide (185 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (51 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[S:29](Cl)(=[O:31])=[O:30])[CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:28]=2[N:19]=[CH:20][CH:21]=[CH:22]3)(=[O:30])=[O:31])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1cccc2cccnc12)c1cccc2cccnc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
The product has already been described in: V. M. Dziomko et al., Azotsoderzhashchie Geterotsikly 1967, 281-284; but by a different method of synthesis. Several grains of activated 4 Å molecular sieve are added to a solution under argon of 8-aminoquinoline (200 mg; 1.39 mmol) and triethylamine (0.30 ml; 2.15 mmol) in 10 ml of CHCl3 and the mixture is stirred slowly for 1 hour. 8-quinolinesulfonyl chloride (350 mg; 1.54 mmol) is added and the mixture is heated to 65° C. for 15 hours. After cooling, 50 ml of CHCl3 are added and the mixture is washed in water (2×50 ml) then dried over anhydrous Na2SO4 and the solvent is evaporated under reduced pressure. The solid is washed with 5 ml of CH2Cl2 to yield after drying 25 in the form of a beige powder (108 mg; 0.32 mmol, yield=23%). NMR-1H (250 MHz, DMSO-d6) δ, ppm: 10.44 (s, 1H); 9.11 (dd, 3J (H, H)=4.5 Hz, 4J (H, H)=1.5 Hz, 1H); 8.83 (dd, 3J (H, H)=4.0 Hz, 4J (H, H)=1.5 Hz, 1H); 8.47 (dd, 3J (H, H)=7.5 Hz, 4J (H, H)=1.5 Hz, 1H); 8.40 (dd, 3J (H, H)=8.5 Hz, 4J (H, H)=1.5 Hz, 1H); 8.22 (dd, 3J (H, H)=8.0 Hz, 4J (H, H)=1.5 Hz, 1H); 8.20 (dd, 3J (H, H)=8.0 Hz, 4J (H, H)=1.5 Hz, 1H); 7.80 (dd, 3J (H, H)=7.5 Hz, 4J (H, H)=1.5 Hz, 1H); 7.70 (dd, 3J (H, H)=8.0 and 7.5 Hz, 1H); 7.62 (dd, 3J (H, H)=8.5 and 4.5 Hz, 1H); 7.51 ((dd, 3J (H, H)=8.5 and 4.0 Hz, 1H); 7.50 (dd, 3J (H, H)=8.5 Hz, 4J (H, H)=1.0 Hz, 1H); 7.42 (dd, 3J (H, H)=8.0 and 7.5 Hz, 1H). NMR-13C (63 MHz, DMSO-d6) δ, ppm: 151.5 (CH); 148.9 (CH); 142.1 (Cq); 137.6 (Cq); 136.9 (CH); 136.3 (CH); 134.4 (CH); 134.2 (Cq); 133.7 (Cq); 131.7 (CH); 128.2 (Cq); 127.8 (Cq); 126.6 (CH); 125.5 (CH); 122.6 (CH); 122.3 (CH); 122.1 (CH); 113.8 (CH). MS (CID, NH3): m/z=336 (MH+). Analysis (%) for C18H13N3O2S.0.2H2O: calculated C, 63.78. H, 3.98. N, 12.40. found C, 63.53. H, 3.70. N, 12.23.
Reaction SMILES: [C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([N:10]=[CH:11][C:12]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>CCOC(C)=O.[OH-].[Pd+2].[OH-]>[C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([NH:10][CH2:11][CH:12]([NH:16][S:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)(=[O:18])=[O:19])[CH2:13]3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Nc1cnc2nn(-c3ccccc3)cc2c1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=S(=O)(NC1CNc2nn(-c3ccccc3)cc2C1)c1ccccc1
Reaction time: 5 h

Procedure:
A suspension of 3D (50 mg, 0.142 mmol) and palladium hydroxide (20% wt of Pd) on carbon (50 mg) in EtOAc (5 mL)/methanol(2 mL) was stirred under a hydrogen balloon for 5 hours, then filtered via a pad of Celite. The filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with 2.0 M NH3 in MeOH/CH2Cl2 (3:97 ratio) to give the desired product, which was further purified using preparative HPLC to give the title compound as a TFA salt (15 mg, 22% yield). LC/MS (method A): retention time=2.75 min, (M+H)+=355.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]([OH:13])(=[O:12])[CH:10]=[O:11]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[OH:8])[CH:10]([OH:11])[C:9]([OH:13])=[O:12]
Reactant: Oc1ccccc1Cl
Reactant: O=CC(=O)O
Product: O=C(O)C(O)c1ccc(O)c(Cl)c1

Procedure:
o-chlorophenol is reacted with glyoxylic acid to give 3-chloro-4-hydroxymandelic acid,
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[O:6].[N+:11]([CH:13](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:14])#[C-:12].C([O-])([O-])=O.[K+].[K+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:12]=[N:11][C:13]=2[CH3:14])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1ccc(C=O)cc1F
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccc(-c2ocnc2C)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A mixture of 3-fluoro-4-methylbenzaldehyde (1.38 g, 10.0 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (2.09 g, 10.0 mmol), and K2CO3 (1.66 g, 12.0 mmol) in 50 mL methanol was heated at reflux 3 hr, then cooled to room temperature and stirred overnight. The reaction mixture was concentrated and the residue taken up in 25 mL H2O and 25 mL Et2O. The water layer was extracted with Et2O, and the organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (Analogix® SF40-115 g column) with 15% EtOAc/hexanes to yield 1.56 g (82%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.45-7.30 (m, 3H), 2.36 (s, 3H), 2.27 (d, J=1.9, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([NH2:12])=[O:11])=[C:4]([N+:18]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:18][C:4]1[CH:3]=[C:2]([Cl:1])[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11]
Reactant: NC(=O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: NC(=O)c1cccc(Oc2ccc(Cl)cc2N)c1
Yield: 120.2 %

Procedure:
The product from Example 171a (0.56 g, 1.9 mmol) was reacted with SnCl2 following the procedure described in Example 1f to give the title compound (0.60 g, 83%).
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH:16][C:32]([CH:29]3[CH2:30][CH2:31][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27][CH2:28]3)=[O:33])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Cc1ccc2c(c1)c1c(n2CCN)CCN(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCNC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.5 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanamine (100 mg, 0.41 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (94 mg, 0.41 mmol), N,N′-dicyclohexylcarbodiimide (93 mg, 0.45 mmol) and 4-dimethylaminopyridine (55 mg, 0.45 mmol) in dry dichloromethane (2.5 ml) were stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated using rotary evaporator to obtain 14 mg of tert-butyl 4-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethylcarbamoyl)piperidine-1-carboxylate after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0. 05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml). The compound obtained was taken in 3 ml of HCl in dioxane and stirred for 1 h to obtain 5 mg of N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)piperidine-4-carboxamide as HCl Salt. 1H NMR (DMSO) 10.78 (bs, 1H), 8.1 (bs, 1H), 7.40 (d, 1H), 7.2 (s, 1H), 7.05 (d, 1H), 4.6-4.2 (m, 1H), 4.3-4.2 (m, 1H), 4.2 (m, 2H), 4.0-3.8 (m, 3H), 3.35-3.05 (m, 4H), 3.0 (s, 3H), 2.95-2.8 (m, 2H), 2.4 (s, 3H), 2.3-2.2 (m, 1H), 2.1-2.00 (m, 1H), 1.8-1.6 (m, 4H).
Reaction SMILES: N1C=CC=CC=1.[N:7]([C@@H:10]1[C@@H:14]([CH2:15][OH:16])[O:13][C@@H:12]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:11]1)=[N+:8]=[N-:9].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)(Cl)Cl>[C:26]([O:16][CH2:15][C@H:14]1[O:13][C@@H:12]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:11][C@@H:10]1[N:7]=[N+:8]=[N-:9])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Reaction time: 8 h

Procedure:
To a pyridine (50 ml) solution of 3'-azido-3'-deoxythymidine (5.0 g, 18.7 mmole) 1 was added acetic anhydride dropwise in an ice-water bath. The mixture was allowed to stand overnight in the refrigerator. The solution was then poured into CHCl3 (20 ml), washed with H2O (200 ml×2), with a saturated solution of sodium bicarbonate and then H2O (200 ml×2). The organic layer was then dried (MgSO4). After removing the solvent, a syrup (6.5 g) was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH2:3][OH:4]>ClCCl.CS(C)=O>[CH3:1][C:2]([CH3:13])([CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH:3]=[O:4]
Reactant: CC(C)(CO)COC1CCCCO1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C=O)COC1CCCCO1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2,2-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)propan-1-ol (20 g, 106 mmol) an TEA (44.4 mL, 319 mmol) in dry dichloromethane (300 mL) cooled in an ice bath to 0° C.±5° C. was added a solution of sulfur trioxide pyridine complex (50.7 g, 319 mmol) in anhydrous DMSO (300 mL) in one portion. There was an exotherm to 27° C. The bath was removed and the mixture allowed to stir for 20 minutes at room temperature after which time conversion was complete by TLC. The reaction was quenched with 225 mL of saturated NaHCO3, concentrated on the rotovap to remove dichloromethane and extracted with 3×200 mL of ethyl acetate. The combined extracts were washed once with 250 mL of 10% citric acid, dried over MgSO4 and concentrated. Drying under vacuum gave 2,2-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)propanal as an oil. Contains ˜40% DMSO by NMR: 1H NMR (400 MHz, CDCl3) δ 9.6 (s, 1H), 4.6 (m, 1H), 3.8 (d, 1H), 3.5 (m, 1H), 3.38 (d, 1H), 1.8-1.4 (min, 6H), 1.06 (s, 3H), 1.04 (s, 3H).
Reaction SMILES: [CH:1]1[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=2[CH:4]=[N:3][CH:2]=1)=[O:8].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:7]([C:6]2[CH:1]=[CH:2][N:3]=[CH:4][C:5]=2[C:10]([OH:9])=[O:11])=[O:8])=[CH:15][CH:14]=1
Reactant: O=C1OC(=O)c2cnccc21
Reactant: Cc1ccc([Mg]Br)cc1
Product: Cc1ccc(C(=O)c2ccncc2C(=O)O)cc1

Procedure:
Employing 3,4-pyridinecarboxylic anhydride (10.0 g) and 4-methylphenyl magnesium bromide, substantially the same reaction and process as in Reference Example 2 Step 1 were conducted to give 4-(4-methylbenzoyl)-3-pyridinecarboxylic acid as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]([F:31])([F:30])[O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]([F:30])([F:31])[O:21][C:22]1[CH:23]=[C:24]([CH2:25][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:27]=[CH:28][CH:29]=1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(OC(F)(F)F)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.7 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (935 mg, 3.85 mM), 3-trifluoromethoxybenzyl bromide (1.0 g, 3.93 mM), and potassium carbonate (531 mg, 3.85 mM) in 20 mL DMF was stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated to afford 1.6 g (100%) of the 9-[(3-trifluoromethoxyphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a foam. 1H NMR (DMSO-d6) δ7.7 (dd, 1H, J=1 and 8 Hz), 7.45 (t, 1H, J=8 Hz), 7.3-7.1 (m, 4H), 7.05 (d, 1H, J=8 Hz), 5.6 (s, 2H), 3.8 (s, 3H), 3.0 (m, 2H), 2.45 (m, 2H), and 2.1 (m, 2H). IR (CDCl3, cm−1) 1729, 1647, 1439, 1259, 1176, and 1116. MS (ES) m/e 418.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[I-].[Na+].Cl[CH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:17]2[CH2:18][CH2:19][C:16]=12.C([OH:25])C>O>[CH:14]([C:15]1[CH:22]=[CH:21][CH:20]=[C:17]2[CH2:18][CH2:19][C:16]=12)=[O:25]
Reactant: ClCc1cccc2c1CC2
Reactant: CCO
Agent: C1N2CN3CN1CN(C2)C3
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: O=Cc1cccc2c1CC2
Reaction time: 2.5 h

Procedure:
To a hot solution of hexamethylene tetramine (14 g) and sodium iodide (16 g) in 140 g of ethanol was added 4-chloromethylbenzocyclobutene (15.2 g) with stirring. After standing at ambient temperature for 2-3 h, the mixture was diluted with 150 ml of water and then heated at reflux for 2 h. The resulting mixture was steam distilled and the distillate was extracted three times with ether. The combined ether extract was washed with water, dried over magnesium sulfate, and fractionally distilled to give 4-formylbenzocyclobutene: 1H NMR (CDCl3) δ 3.17 (s, 4), 7.15 (d, 1), 7.51 (s, 1), 7.67 (d, 1) and 9.86 ppm (s, 1).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=1[CH2:4][O:5][C:6](=[O:17])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][CH3:9].[CH2:26]([O:28][C:29](=[O:48])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:27].C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:26]([O:28][C:29](=[O:48])[CH2:30][C:31]1[CH:32]=[C:33]([C:2]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=2[CH2:4][O:5][C:6](=[O:17])[N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH3:9])[C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)[CH3:27]
Reactant: CCN(Cc1ccccc1)C(=O)OCc1cc(C(F)(F)F)ccc1Br
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2COC(=O)N(CC)Cc2ccccc2)c1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
Benzyl-ethyl-carbamic acid 2-bromo-5-trifluoromethyl-benzyl ester (0.354 g, 0.85 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (0.300 g, 0.94 mmol), and potassium carbonate (0.410 g, 2.98 mmol) were combined in a deoxygenated solution of DME (8 mL) and H2O (4 mL). Tetrakis(triphenylphosphine)palladium(0) (0.100 g, 0.09 mmol) was added, and the reaction was stirred at 75° C. for 2 hours. After work-up, the crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>CCOCC>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[C:18]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[C:6]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[N:7]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Product: CN1CCC(c2nn(C(=O)c3ccccc3)c3cc(F)ccc23)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 50.9 %

Procedure:
A mixture of 3.1 g of 6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole and 8 ml of benzoyl chloride was heated at 100° C. in a steam bath for 8 hrs. After cooling, ether was added and the solid was collected. The solid was treated with ammonium hydroxide solution to give an oil. The oil was dissolved in 300 ml of ether, stirred and 1.2 g of fumaric acid was added. After four hrs at ambient temperature, the fumarate salt was collected. Recrystallization from ethanol-ether yielded 3.0 g (50.9%) of product, mp 180°-182° C.
Reaction SMILES: [C:1]1(=[O:15])[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][CH2:13][N:4]3[C:3](=[O:14])[NH:2]1)[CH:7]=[CH:8][CH:9]=2.CS(O[CH2:21][CH2:22][CH2:23][C@@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:31]=[CH:32][C:33]3[S:38][CH2:37][C:36](=[O:39])[NH:35][C:34]=3[CH:40]=2)[CH2:25]1)(=O)=O>>[O:29]=[C:27]1[N:26]([C:30]2[CH:31]=[CH:32][C:33]3[S:38][CH2:37][C:36](=[O:39])[NH:35][C:34]=3[CH:40]=2)[CH2:25][C@H:24]([CH2:23][CH2:22][CH2:21][N:2]2[C:1](=[O:15])[C:10]3[C:5]4=[C:6]([CH2:11][CH2:12][CH2:13][N:4]4[C:3]2=[O:14])[CH:7]=[CH:8][CH:9]=3)[O:28]1
Reactant: CS(=O)(=O)OCCC[C@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Reactant: O=c1[nH]c(=O)n2c3c(cccc13)CCC2
Product: O=C1CSc2ccc(N3C[C@H](CCCn4c(=O)c5cccc6c5n(c4=O)CCC6)OC3=O)cc2N1
Yield: 25 %

Procedure:
Starting from 6,7-dihydropyrido[3,2,1-ij]quinazoline-1,3(2H,5H)-dione (prepared according to WO 01/79206) and 6-[(5S)-5-[3-[(methylsulfonyl)oxy]propyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzothiazin-3(4H)-one (prepared according to WO 2010/041194) and using Procedure E, the title compound was obtained as a colourless solid (48 mg; 25% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](Cc1cccnc1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) and methyl (S)-2-amino-3-(3-pyridyl)propionate hydrochloride (Synthetech), the title compound was prepared as a solid (mp 101-103° C.). The reaction was monitored by tlc (Rf=0.48 in 10% MeOH/DCM) and the product was purified by silica gel column chromatography.
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH-].[K+].[CH2:25](I)[CH3:26]>CS(C)=O>[CH2:25]([O:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:26]
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Temperature: 0 °C
Yield: 80 %

Procedure:
A mixture of racemic ethyl 2-hydroxy-3-(4-benzyloxyphenyl)propionate of the formula (10) (70 g) obtained according to the procedure described in step (iii) above. potassium hydroxide (26 g), dimethylsulphoxide (280 ml) and molecular sieves (36 g) was stirred at room temperature for 15 minutes. Ethyliodide (110 g) was added slowly at room temperature over 15 minutes. The reaction was stirred at the same temperature for a period of 15–20 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was dumped into ice water and extracted with toluene. The combined organic extracts were washed with water and the solvent was removed under reduced pressure to afford title compound of the formula (12a) (61–63 g, 80–82%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: Nc1cccc(Cl)c1
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)Nc2cccc(Cl)c2)cc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A mixture of the product obtained in 434a (11.6 g, 52.0 mmol) in 150 mL THF was added to a stirred mixture of 3-chloro-aniline (5.8 mL, 54.6 mmol) and TEA (10 mL, 72 mmol) in 100 mL THF under nitrogen. After stirring for 16 h, the mixture was filtrated, washed with THF and evaporated to dryness. The residue was triturated with methanol, filtrated and dried at 55° C.
Reaction SMILES: [C:1]12([C:11]([OH:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Al+3].[Cl-].[Cl-].[Cl-].[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][C:3]12[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][C:1]([C:11]([OH:13])=[O:12])([CH2:8]3)[CH2:2]1)[CH2:4]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: O=C(O)C12CC3CC(CC(Br)(C3)C1)C2
Temperature: 5 °C
Reaction time: 48 h
Yield: 75.6 %

Procedure:
More specifically, adamantane-1-carboxylic acid (1) (45 g, 0.25 mol) was added to mixture of AlCl3 (45 g, 0.34 mol) and Br2 (450 g) at 0° C. and stirred at 0-10° C. for 48 hrs, kept 5 hrs at about 20° C., poured on to 500 g crushed ice, diluted with 300 ml CHCl3 and decolorized with solid Na2S2O5. The aqueous phase was extracted with Et2O (50 ml×2). The combined organic solution was washed with H2O and extracted with 10% NaOH. The alkaline extraction was acidified with 2N H2SO4 and provided 49 g (yield=75.7%) of 3-bromo-adamantane-1-carboxylic acid (2).