Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Br)C1C=CC=CC=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.[C:21]([C:24]1[S:28][C:27]([N:29]2[CH2:33][CH2:32][NH:31][C:30]2=[O:34])=[N:26][C:25]=1[CH3:35])(=[O:23])[CH3:22]>>[C:21]([C:24]1[S:28][C:27]([N:29]2[CH2:33][CH2:32][N:31]([CH2:15][C:14]3[CH:17]=[CH:18][C:11]([C:10]([F:20])([F:19])[F:9])=[CH:12][CH:13]=3)[C:30]2=[O:34])=[N:26][C:25]=1[CH3:35])(=[O:23])[CH3:22]
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: BrCc1ccccc1
Product: CC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C
Yield: 74 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 4-(trifluoromethyl)benzyl bromide to react with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one, the title compound was obtained in 74% yield: mp 141-142° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 4.54 (s, 2H), 4.13-4.07 (m, 2H), 3.50-3.41 (m, 2H), 2.66 (s, 3H), 2.25 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 190.6, 159.6, 155.9, 155.4, 139.6, 130.2, 128.5, 126.0, 124.8, 122.1, 47.6, 42.0, 41.8, 30.5, 18.2; MS (ES+) m/z 384.1 (M+1).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:7][CH2:8][CH2:9][NH2:10].N1C=CC=CC=1.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>O.C1C=CC=CC=1>[Cl:17][CH:18]([Cl:22])[C:19]([N:10]1[C:1]2([CH2:5][CH2:4][CH2:3][CH2:2]2)[S:7][CH2:8][CH2:9]1)=[O:20]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: NCCS
Reactant: O=C1CCCC1
Solvent: c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(C(Cl)Cl)N1CCSC12CCCC2

Procedure:
From a boiling mixture of 8.4 g. (0.1 moles) of cyclopentanone and 7.7 g. (0.1 mole) of 2-mercaptoethylamine in 100 ml. of benzene the water formed is continuously distilled off. Boiling is continued until 1.8 ml. of water are separated. The reaction mixture is then cooled and 8 g. (0.1 moles) of pyridine are added followed by a dropwise addition of 14.7 g. (0.1 moles) of dichloroacetyl chloride, with external salt/ice cooling.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:28])=[CH:16][C:17]([N:18]3[CH2:27][CH2:26][C:21]4(OCC[O:22]4)[CH2:20][CH2:19]3)=[C:12]2[C:11]([CH3:29])=[C:10]1[CH3:30].C(=O)([O-])O.[Na+]>Cl.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:28])=[CH:16][C:17]([N:18]3[CH2:27][CH2:26][C:21](=[O:22])[CH2:20][CH2:19]3)=[C:12]2[C:11]([CH3:29])=[C:10]1[CH3:30]
Reactant: Cc1cc(N2CCC3(CC2)OCCO3)c2c(C)c(C)n(-c3ccc(Cl)cc3Cl)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(N2CCC(=O)CC2)c2c(C)c(C)n(-c3ccc(Cl)cc3Cl)c2n1
Reaction time: 8 h
Yield: 81.6 %

Procedure:
After 1-(2,4-dichlorophenyl)-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]-pyridine (5.21 g) was stirred in a mixture of 4 M hydrochloric acid (60 mL) and tetrahydrofuran (60 mL) at room temperature for 2.5 hours, 6 M hydrochloric acid (30 mL) was added thereto and the resulting mixture was stirred overnight. After completion of the reaction, the reaction mixture was poured into a saturated aqueous sodium hydrogen-carbonate solution and extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, after which the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The crystals thus obtained were washed with ethyl acetate to obtain 1-(2,4-dichlorophenyl)-4-(4-oxopiperidin-1-yl)-2,3,6-trimethyl-1H-pyrrolo[2,3-b]pyridine (3.83 g).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=C(C2C=CC=CC=2)C(C2C=CC=CC=2)=[N:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]([C:51]([C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)=O)=O)=[CH:45][CH:44]=1>>[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[C:51]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=3)=[N:22][C:21]3[C:26](=[CH:27][CH:28]=[C:19]([C:8]4[N:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[C:11]5[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=5[N:9]=4)[CH:20]=3)[N:25]=2)=[CH:45][CH:44]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)c(-c4ccccc4)nc3c1)n2C1CCCCC1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2nc3ccc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)cc3nc2-c2ccc(OC)cc2)cc1

Procedure:
Prepared as described for Compound 406 using 4,4′-dimethoxybenzil in place of benzil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:30]([O-])([N+]([O-])=O)=[O:31]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:30]=[O:31])[C:5]([N:7]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CC(C)(C)CN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)CN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 74.5 %

Procedure:
3.6 g of 1-(2-chloroethyl)-3-neopentyl-3-D-galactopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.9 g of 1-(2-chloroethyl)-1-nitroso-3-neopentyl-3-D-galactopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[NH:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[C:45]([CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)=[O:46].C(N(C(C)C)CC)(C)C.C(#N)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:50]2[CH2:51][CH2:52][CH:47]([C:45]([C:37]3[NH:36][C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[N:38]=3)=[O:46])[CH2:48][CH2:49]2)([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: COc1ccc(C2(CCS(C)(=O)=O)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Reactant: O=C(c1nc2ccccc2[nH]1)C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(C2(CCN3CCC(C(=O)c4nc5ccccc5[nH]4)CC3)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dimethoxy-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine (1.19 g, 2.27 mmol), 4-[1H-benzoimidazole-2-carbonyl]-piperidine (1.65 g, 3.41 mmol) and diisopropylethylamine (1.47 g, 11.35 mmol) and acetonitrile (11 mL). Reflux the reaction mixture overnight, dilute with ethyl acetate and extract successively with a saturated aqueous NH4Cl solution, 5% aqueous NaHCO3 solution, water and saturated aqueous NaCl solution. Separate the organic layer, dry over anhydrous Na2So4, filter and remove the solvent in vacuo. Chromatograph the residue on silica gel eluting with ethyl acetate/methanol (5/1), evaporate the solvent and dry overnight at 82° C. at 0.20 torr to yield title compound: mp; 113.0-116.0° .C, Rf=0.23 (silica gel, 5/1 ethyl acetate/methanol). Elemental Analysis calculated for C37H44N4O7: C 67.66; H 6.75; N 8.53; Found: C 67.00; H 6.77; N 8.39.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10].[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:11]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10])(=[O:13])[CH3:12]
Reactant: C#CCN1CC[C@@H](O)C1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCN1CC[C@@H](OC(C)=O)C1=O

Procedure:
The title compound is prepared by the procedure of Example 52 using 19.6 g of (R)-3-hydroxy-1-(2-propynyl)-2-pyrrolidinone, 26.6 ml of acetic anhydride, 17 ml of pyridine, 0.6 g of 4-(dimethylamino)pyridine and 200 ml of methylene chloride to give 23.4 g of the desired product as a pale yellow oil. [α]D26° =+59° (methylene chloride).
Reaction SMILES: [CH2:1]([C:8](C(OCC)=O)([CH2:14][C:15]#[C:16][CH3:17])[C:9]([O:11]CC)=[O:10])[C:2]1C=CC=C[CH:3]=1.C(C(CC#CC)C(O)=O)C1C=CC=CC=1>>[CH2:1]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[C:9]([OH:11])=[O:10])[C:2]#[CH:3]
Reactant: CC#CCC(Cc1ccccc1)(C(=O)OCC)C(=O)OCC
Agent: CC#CCC(Cc1ccccc1)C(=O)O
Product: C#CCC(CCCC)C(=O)O

Procedure:
Proceeding similarly, but replacing ethyl 2-carboethoxy-2-propargylhexanoate with ethyl 2-benzyl-2-carboethoxy-4-hexynoate, 2-benzyl-4-hexynoic acid is prepared.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10](Cl)(=[O:12])=[O:11])[CH:9]=1.Cl.[NH2:17][CH2:18][C:19]([NH2:21])=[O:20].C(N(CC)C(C)C)(C)C>O1CCOCC1.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10]([NH:17][CH2:18][C:19]([NH2:21])=[O:20])(=[O:12])=[O:11])[CH:9]=1
Reactant: NCC(N)=O
Reactant: COc1ccc(CCCl)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCCl)cc1S(=O)(=O)NCC(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-(2-chloro-ethyl)-2-methoxy-benzenesulfonyl chloride (5.78 g, 21.5 mmol) is dissolved in dioxane (72 mL). To this solution is added glycinamide hydrochloride (4.75 g, 42.9 mmol) and N,N-diisopropylethylamine (7 mL, 42.9 mmol) with stirring at room temperature for 24 h. The solution is diluted with ethyl acetate (100 mL) and washed with 1 M H3PO4 (2×50 mL), sat NaHCO3, (1×50 mL,) brine (1×50 mL). The organic phase is dried with Na2SO4, filtered and the volatiles concentrated to a white solid. The solid is collected on a buchner by vacuum filtration and washed with ether to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH2:18][C:19]([NH2:21])=[O:20].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CS(C)=O.C1COCC1.O>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH2:18][C:19]([NH2:21])=[O:20])[CH3:32]
Reactant: CCOC(=O)CCCBr
Reactant: NC(=O)Cc1cn(Cc2ccccc2)c2ccc(O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)cn2Cc1ccccc1
Temperature: 60 °C
Yield: 65.9 %

Procedure:
A solution of 280 mg (1.0 mmol) of 5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide in 30 mL of DMSO and 10 mL of THF was treated with 45 mg (1.1 mmol) of 60% NaH/mineral oil, and then with 0.16 mL (1.1 mmol) of ethyl 4-bromobutyrate. The mixture was heated in an oil bath at 60° C. for 2.25 hours. It was diluted with water, extracted with EtOAc, the EtOAc solution washed with water, saturated NaCl solution, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica (CH2Cl2→3% MeOH/CH2Cl2)to give 260 mg (66% yield) of 4-[[3-(2-amino-2-oxoethyl)-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:46]([CH3:47])=[CH:45][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([CH:34]4[CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35]4)[N:29]=[CH:28]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].Cl.CCOC(C)=O>C(O)(C)C.O1CCOCC1>[NH:36]1[CH2:37][CH:34]([N:30]2[C:31]3[C:27](=[CH:26][C:25]([C:21]4[CH:20]=[C:19]([C:17]5[S:18][C:14]6[C:13]([C:48]7[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=7)=[C:12]([C@H:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:46]([CH3:47])=[CH:45][C:15]=6[N:16]=5)[CH:24]=[CH:23][N:22]=4)=[CH:33][CH:32]=3)[CH:28]=[N:29]2)[CH2:35]1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(cnn5C5CN(C(=O)OC(C)(C)C)C5)c4)c3)sc2c1-c1ccc(Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(cnn5C5CNC5)c4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of (S)-tert-butyl 3-(5-(4-(6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)pyridin-2-yl)-1H-indazol-1-yl)azetidine-1-carboxylate (54 mg, 0.070 mmol) in isopropanol (3 mL) was added HCl in Dioxane (3 mL, 4 N in dioxane). The reaction mixture was stirred at room temperature. After the reaction finished, the reaction mixture was diluted by EtOAc, washed by saturated NaHCO3, back-extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down, purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C37H36ClN5O3S: 666.2 (M+H+); found: 666.3.
Reaction SMILES: CO.O1[CH2:8][CH2:7][O:6][CH2:5]C1.Cl.[Cl:10]C1[N:16]=[CH:15][N:14]=[C:13]([N:17]2[C:21](=[O:22])[C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:19][NH:18]2)C=1>C1COCC1>[ClH:10].[CH3:5][O:6][C:7]1[N:16]=[CH:15][N:14]=[C:13]([N:17]2[C:21](=[O:22])[C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:19][NH:18]2)[CH:8]=1
Reactant: C1COCCO1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(-n2[nH]cc(-n3ccnn3)c2=O)ncn1

Procedure:
0.3 ml (6.6 mmol) methanol are initially introduced into 15 ml dioxane. 1.3 ml (2.7 mmol) of a 2 M solution of the phosphazene base P2-tert-butyl in THF are added slowly, while stirring, and the mixture is stirred at RT for 15 min 350 mg (1.3 mmol) of the compound from Example 52A are subsequently added and the mixture is reacted in a single mode microwave (CEM Explorer) at 150° C. for 2 h. A further 2 ml (49.2 mmol) methanol are then added and the mixture is reacted again in a single mode microwave (CEM Explorer) under the same conditions for 2 h. After cooling, the reaction mixture is concentrated and the residue is purified via preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions are combined and the mixture is concentrated on a rotary evaporator. The residue is dried under a high vacuum and 3 ml of a 4 N solution of hydrogen chloride in dioxane is subsequently added. The mixture is stirred at RT for 30 min and the solid is then filtered off and dried under a high vacuum.
Reaction SMILES: [H-].[Na+].[CH:3](OCC)=[O:4].[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][C:15]2=[O:21].Cl>C1COCC1.O.CO>[F:20][C:17]1[CH:18]=[CH:19][C:10]([O:9][CH3:8])=[C:11]2[C:16]=1[C:15](=[O:21])[CH:14]([CH:3]=[O:4])[CH2:13][CH2:12]2
Reactant: COc1ccc(F)c2c1CCCC2=O
Reactant: CCOC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c2c1CCC(C=O)C2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 113.1 %

Procedure:
Sodium hydride (12.7 g) (50% dispersion, washed with hexane) was suspended in dry THF under nitrogen. Ethyl formate (27 g) was added and the mixture was stirred for 20 minutes in an ice/water bath. 5-Methoxy-8-fluoro-1-tetralone (J. Med. Chem. (1973) 1003) (17 g) dissolved in THF was added and the mixture was allowed to warm to room temperature. The mixture was stirred under nitrogen for 24 hours. Methanol was added followed by water. The mixture was poured into water, acidified with conc. HCl (aq) and extracted into CHCl3. The organic phase was dried (MgSO4), filtered and concentrated to give a dark oil (22 g) which solidified on standing. This material was recrystallised from ethyl acetate/hexane to give the above compound, m.p. 66°-68° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@:8]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])([CH3:15])[CH2:9][S:10][CH2:11][C:12](O)=[O:13])[CH:7]=1.C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@@:8]2([CH3:15])[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH3:27])[C:12](=[O:13])[CH2:11][S:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(CN[C@@](C)(CSCC(=O)O)c2cc(Br)ccc2F)c(OC)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)CSC[C@@]2(C)c2cc(Br)ccc2F)c(OC)c1
Yield: 92.8 %

Procedure:
To a solution of (R)-2-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino) propylthio)acetic acid (3.3 g, 6.99 mmol, Eq: 1.00) and N,N-diisopropylethylamine (2.71 g, 3.66 ml, 21.0 mmol, Eq: 3.0) in ethyl acetate (194 ml) was added at 23° C. 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate) (6.67 g, 6.23 ml, 10.5 mmol, Eq: 1.5) and the colourless reaction solution was stirred at 23° C. for 2 hours. The reaction mixture was washed with sat NaHCO3-sol., water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the nearly pure (R)-5-(5-bromo-2-fluorophenyl)-4-(2,4-dimethoxybenzyl)-5-methylthiomorpholin-3-one (2.95 g, 6.49 mmol, 92.9% yield) as a colourless oil, which crystallized in the fridge and was used without further purification. MS (ISP): m/z=454.0 [M+H]+ and 456.1 [M+2+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:54]([CH3:56])[CH3:55])[C:7]([N:9]1[C@H:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[C:31]5C(=CC=4)C4NC([C@@H]6CCCN6C(OC(C)(C)C)=O)=NC=4[CH:33]=[CH:32]5)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:11]2(OCCO2)[CH2:10]1)=[O:8])=[O:4].Br[C:58]1C=C2C(=C[CH:67]=1)C=C(C1NC([C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)C)=NC=1)C=C2.BrC1C=C[C:93]([C:96]2[NH:100][C:99]([C@@H:101]3[CH2:105][O:104][CH2:103][N:102]3[C:106]([O:108][C:109]([CH3:112])([CH3:111])[CH3:110])=[O:107])=[N:98][CH:97]=2)=[CH:92][CH:91]=1.BrC1C=CC(C2NC([C@@H]3CC4(OCCO4)CN3C(=O)[C@@H](NC(=O)OC)C(C)C)=NC=2)=CC=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.BrC1C=C2C(=CC=1)C1NC([C@@H]3CCCN3C(OC(C)(C)C)=O)=NC=1C=C2>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:54]([CH3:55])[CH3:56])[C:7]([N:9]1[CH2:10][CH2:11][CH2:16][C@H:17]1[C:18]1[NH:19][C:20]([C:23]2[CH:28]=[C:27]3[C:26](=[CH:25][CH:24]=2)[CH:29]=[C:30]([C:31]2[CH:91]=[CH:92][C:93]([C:96]4[NH:100][C:99]([C@@H:101]5[CH2:105][O:104][CH2:103][N:102]5[C:106]([O:108][C:109]([CH3:112])([CH3:111])[CH3:110])=[O:107])=[N:98][CH:97]=4)=[CH:33][CH:32]=2)[CH:67]=[CH:58]3)=[CH:21][N:22]=1)=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)N1COC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5c(ccc6nc([C@@H]7CCCN7C(=O)OC(C)(C)C)[nH]c65)c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(Br)cc3)[nH]1)OCCO2)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6COCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C

Procedure:
The title compound was prepared according to the method employed to prepare (S)-Tert-butyl 2-(7-(4-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate, except that, respectively, methyl (S)-1-((S)-2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate and (R)-tert-butyl 4-(5-(4-bromophenyl)-1H-imidazol-2-yl)oxazolidine-3-carboxylate were used instead of methyl (S)-1-((S)-8-(5-(4-bromophenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate (100 mg, 0.197 mmol), bis(pinacolato)diboron and (S)-tert-butyl 2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate. MS (ESI) m/z 734.91 [M+H]+. (110 mg, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[C:16]3[N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[I-].[Na+].C(N(CC)CC)C.[CH3:36][O:37][CH2:38][CH2:39]Br>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[C:16]3[N:19]3[CH2:24][CH2:23][N:22]([CH2:39][CH2:38][O:37][CH3:36])[CH2:21][CH2:20]3)=[CH:11][CH:10]=2)=[O:7])=[CH:25][CH:26]=1
Reactant: COCCBr
Reactant: O=C(Nc1ccc2cccc(N3CCNCC3)c2c1)c1ccc(Cl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCN1CCN(c2cccc3ccc(NC(=O)c4ccc(Cl)cc4)cc23)CC1

Procedure:
A mixture of 7-(4-chlorobenzamido)-1-(1-piperazinyl)-naphthalene (0.15 g, 0.41 mmol, product of example 12), sodium iodide (0.064 g, 0.431 mmol), triethylamine (0.164 mL, 0.431 mmol) and 2-bromoethyl methyl ether (0.040 mL, 0.431 mmol) in acetonitrile (7 mL) was refluxed overnight. The reaction was cooled and concentrated at reduced pressure. The residue was taken up in methylene chloride and washed with 1N sodium hydroxide and brine, dried, concentrated onto silica gel and flash chromatographed (1×2.5 inches). Elution proceeded as follows: 50% ethyl acetate hexane (100 mL) and 75% ethyl acetate/hexane (100 mL), nil; 75% ethyl acetate/hexane (100 mL) and ethyl acetate (150 mL), 0.121 g (69%) of 7-(4-chlorobenzamido)-1-(4-methoxyethyl-1-piperazinyl)-naphthalene as an oil. This oil was converted to the HCl salt from an ether solution. An amorphous white powder hydrochloride salt of the title compound was obtained. mp 134°-148° C. 1H NMR δ 8.54 (br s, 1 H), 8.05 (br s, 1 H), 7.84 (long range coupled t, J=9 Hz, 3 H), 7.66 (dd, J -2, 9 Hz, 1 H), 7.55-7.43 (m, 3 H), 7.36 (t, J=8 Hz, 1 H), 7.11 (dd, J=1, 7.5 Hz, 1 H), 3.57 (t, J=5.5 Hz, 2H), 3.38 (s, 3 H), 3.19 (br s, 4 H), 2.83 (br s, 4 H), 2.70 (t, J=5.5 Hz, 2 H). Analysis calculated for C24H26ClN3O2 ·2HCl·1.5H2O: C, 55.02; H, 5.96; N, 8.02. Found: C, 55.53; H, 6.31; N, 7.78.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][NH:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])C.C(OC(C1(NC(C2CC(OC3C4C(=CC(OC)=CC=4)N=C(C4C=CC=CC=4)C=3)CN2C(=O)NC([C:82](=[O:94])[NH:83][CH:84]2[C:92]3[C:87](=[CH:88][CH:89]=[CH:90][CH:91]=3)[CH2:86][CH:85]2[OH:93])C(C)(C)C)=O)CC1C=C)=O)C.C1C2C(=CC=CC=2)[C@H](N)[C@@H]1O.OC1CC2C(=CC=CC=2)C1NC(C(N1CC(OC2C3C(=CC(OC)=CC=3)C=C(C3C=CC=CC=3)C=2)CC1C1(C(O)=O)CC1C=C)C(C)(C)C)=O>>[OH:93][C@@H:85]1[CH2:86][C:87]2[C:92](=[CH:91][CH:90]=[CH:89][CH:88]=2)[C@@H:84]1[NH:83][C:82]([N:15]1[CH2:16][C@H:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:21]=2)[CH2:18][C@H:14]1[C:12]([NH:11][C@:6]1([C:4]([OH:3])=[O:5])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:13])=[O:94]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1)C(=O)OCC
Agent: C=CC1CC1(C(=O)O)C1CC(Oc2cc(-c3ccccc3)cc3cc(OC)ccc23)CN1C(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Agent: N[C@H]1c2ccccc2C[C@H]1O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(=O)O

Procedure:
Compound 12 was treated as described for the preparation of 13 but with the use of (1S,2R)-cis-1-amino-2-indanol instead of 2-amino-N-(2-hydroxyindan-1-yl)-3,3-dimethyl butyramide followed by ester hydrolysis as described for the preparation of compound 14 which gave the title compound. Purity by HPLC>95%. M+H+649.1.