Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[S:18][C@H:17]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[CH2:16][S:15]2)[CH:6]=[C:7]([N+:11]([O-])=O)[C:8]=1[O:9][CH3:10].[Cl-].[Ca+2].[Cl-]>C(O)C.O.[Zn]>[NH2:11][C:7]1[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([C@H:14]2[S:18][C@H:17]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[CH2:16][S:15]2)[CH:6]=1
Reactant: COc1cc([C@@H]2CS[C@@H](c3cc(OC)c(OC)c([N+](=O)[O-])c3)S2)cc(OC)c1OC
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: COc1cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc(N)c1OC

Procedure:
Trans-2-(3,4-dimethoxy-5-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane (2) (FIG. 20) (3.10 g, 6.84 mmole) was predissolved in 33 ml absolute ethanol. To this solution was added calcium chloride (0.721 g, 6.50 mmole) predissolved in 7 ml H2O followed by freshly activated zinc dust (10.0 g,195 mmole). The reaction was refluxed for 12 hours. The solid was removed by vacuum filtration through celite and was washed with ethyl acetate. The filtrate was washed with H2O, dried over MgSO4, and evaporated in vacuo to a white foam (2.52 g, 87%).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:15]3[N:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][N:16]=3)[CH:5]=[CH:4][C:3]1=2.[H-].[Na+].[CH2:29](I)[CH2:30][CH3:31].O>CN(C=O)C>[CH2:29]([N:14]([C:15]1[N:16]=[CH:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:20]=1)[C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)[CH2:30][CH3:31]
Reactant: CCCI
Reactant: CCOC(=O)c1cnc(Nc2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ncc(C(=O)OCC)cn1
Yield: 63 %

Procedure:
Ethyl 2-[N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)amino]-pyrimidine-5-carboxylate (165 mg) was dissolved in dry DMF (3 ml), and the solution was added with a suspension of NaH (130 mg) in DMF (2 ml). Then, the mixture was added with n-propyl iodide (0.5 ml) and stirred. After the disappearance of the materials was observed with TLC, the reaction mixture was poured into water, and extracted with CH2Cl2. The organic layer was dried over Na2SO4, and the solvent was evaporated. The residue was purified by silica gel flash column chromatography (n-hexane: AcOEt=20:1) to obtain ethyl 2-[N-n-propyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)amino]pyrimidine-5-carboxylate (116.5 mg, 63%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][S:9](=[O:23])(=[O:22])[C:10]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:11]=2[C:12]=1[OH:13])=[O:6].[CH3:24]I>O.CO>[CH3:3][O:4][C:5]([C:7]1[N:8]([CH3:24])[S:9](=[O:23])(=[O:22])[C:10]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:11]=2[C:12]=1[OH:13])=[O:6]
Reactant: CI
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Temperature: 40 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
A solution of 8.2 gm (0.205 mol) of sodium hydroxide in 200 ml of water wasadded dropwise over a period of 40 minutes at a reaction temperature of 20°-25° C to a suspension of 61.0 gm (0.2 mol) of 4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 85.1 gm (0.6 mol) of methyl iodide in 500 ml of methanol. After stirring it for 4 hours, the mixture was cooled to +5° C, and the precipitate (= 50 gm of crude product) was suction-filtered off and washed with ice-cold methanol. The combined methanolic solutions were heated at 40° C for 15 minutes and then evaporated in vacuo until onset of crystallization. An additional 9 gm of crude product were obtained by suctionfiltration and washing with ice-coldmethanol. Recrystallization of the combined crude products from ethylene chloride yielded 53.3 gm (85% of theory) of 4 -hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide, m.p. 229°-230° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:6]([OH:8])[CH:7]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1>CCO>[Cl:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:9][N:10]4[CH2:14][CH2:13][CH2:12][CH2:11]4)=[C:6]([OH:8])[CH:7]=3)=[CH:17][CH:18]=[N:19]2)=[CH:24][CH:23]=1
Reactant: Nc1ccc(CN2CCCC2)c(O)c1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CCO
Product: Oc1cc(Nc2ccnc3cc(Cl)ccc23)ccc1CN1CCCC1
Yield: 42.6 %

Procedure:
5-amino-2-(pyrrolidin-1-ylmethyl)phenol (117 mg, 0.61 mmol) and 4,7-dichloroquinoline (143 mg, 1 eq) were refluxed overnight in 1 mL of EtOH. The reaction mixture was then evaporated and purified by flash chromatography (DCM/MeOH/NH4OH 9:1:0.1) to yield expected compound as a yellow solid (92 mg, 29% yield). LC-MS: m/z (ESI) 354.1-356.1 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([N:29]2[C:37]3[C:32](=[CH:33][C:34]([F:38])=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[O:28])[CH:22]=1.Cl.CC(O)C>CN(C=O)C>[F:38][C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[N:29]([C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:1][C:2]3[CH:3]=[C:4]4[C:17](=[CH:18][CH:19]=3)[CH2:16][C@@:6]3([C:14]5[C:9](=[N:10][CH:11]=[CH:12][CH:13]=5)[NH:8][C:7]3=[O:15])[CH2:5]4)[CH:22]=1)=[O:28])[CH2:30][CH2:31]2
Reactant: Nc1ccc2c(c1)C[C@]1(C2)C(=O)Nc2ncccc21
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(F)ccc21
Agent: Cl
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)C[C@]2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2cc(F)ccc21

Procedure:
0.10 g (0.40 mmol) (S)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 0.11 g (0.40 mmol) (6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 13 μL of a 4 molar aqueous hydrochloric acid solution were added to 2.0 mL of 2-propanol and the mixture was refluxed for 4 h. Then the reaction mixture was dissolved in DMF and purified by preparative HPLC-MS. The product-containing fractions were combined and the organic solvent was evaporated down. The residue was made alkaline with a 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][C:30]#[N:31])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:32].Cl.C(N(CC)CC)C.[N-:41]=[N+:42]=[N-:43].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][C:30]3[NH:43][N:42]=[N:41][N:31]=3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(F)ccc1-c1nc(NCCC#N)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(NCCc2nnn[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 45.4 %

Procedure:
A suspension of the product of Example 206 (200 mg, 0.46 mmol), triethylamine hydrochloride (630 mg, 4.6 mmol) and NaN3 (299 mg, 4.6 mmol) in toluene (20 mL) was heated to toluene reflux for 60 h. Preparative HPLC afforded the title compound 100 mg (45%). LC-MS: 479.0 (MH+, m/z), 1.82 (Rt, min).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][C:16]1([CH2:21][CH2:22][CH2:23][NH2:24])[O:20][CH2:19][CH2:18][O:17]1.C(N(CC)CC)C>ClCCl>[CH3:15][C:16]1([CH2:21][CH2:22][CH2:23][NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[O:20][CH2:19][CH2:18][O:17]1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC1(CCCN)OCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(CCCNc2c([N+](=O)[O-])cnc3ccccc23)OCCO1
Yield: 64.3 %

Procedure:
The general method described in Step 1 of Example 1 was used to react 4-chloro-3-nitroquinoline (45.0 g, 216 mmol), 3-(2-methyl-[1,3]dioxolan-2-yl)propylamine (37.0 g, 255 mmol, prepared as described in PCT Publication WO 01/51486) and triethylamine (37.0 g, 366 mmol) in dichloromethane for 15 hours to provide [3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-(3-nitroquinolin-4-yl)amine (44.1 g) as a yellow solid after recrystallization from a toluene/hexane mixture.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C@H:8]([C:10]([OH:12])=[O:11])[CH3:9].C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([NH:7][C@H:8]([C:10]([OH:12])=[O:11])[CH3:9])=[O:4]
Reactant: CC(Br)C(=O)Cl
Reactant: C[C@H](N)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Br)C(=O)N[C@@H](C)C(=O)O

Procedure:
69.26 g (404 mmol) of α-bromopropionic acid chloride is added in drops at 0° C. to 30 g (336.7 mmol) of alanine and 102.2 g (1010.2 mmol) of triethylamine in 600 ml of methylene chloride. In this case, the temperature remains between 0° C.-5° C. 1000 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated. The organic phase is extracted once more with 400 ml of 5% aqueous hydrochloric acid, dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is recrystallized from acetone/diisopropyl ether.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][CH2:17][C@@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[S:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=3)=[C:26]([F:37])[CH:25]=2)[CH2:19]1.C(N(CC)C(C)C)(C)C.[C:47](O)(=[O:50])[CH2:48][CH3:49]>CN(C=O)C>[F:37][C:26]1[CH:25]=[C:24]([N:20]2[CH2:19][C@H:18]([CH2:17][NH:16][C:47](=[O:50])[CH2:48][CH3:49])[O:22][C:21]2=[O:23])[CH:29]=[CH:28][C:27]=1[C:30]1[S:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=1
Reactant: NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Reactant: CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
1,3-Dicyclohexylcarbodiimide (0.153 g, 0.740 mmol) is added to a mixture of 2-[4-(5(S)-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-4H-[1,3,4]thiadiazin-5-one (0.200 g, 0.617 mmol), N,N-diisopropylethylamine (0.161 ml, 0.927 mmol) and propionic acid (0.051 ml, 0.680 mmol) in DMF (3 ml). The mixture is stirred overnight at room temperature and then partially evaporated under vacuum. The residue is diluted with water (5 ml) and the resulting precipitate is filtered and dried under vacuum. Purification by PTLC (10% MeOH/DCM) gives pure product as a white solid (0.21 g, 90%); 1HNMR (300 MHz, DMSO-d6) δ 0.94 (t, J=7.7 Hz, 3H), 2.08 (q, J=7.7 Hz, 2H), 3.40-3.48 (m, 2H), 3.59 (s, 2H), 3.77 (dd, J=6.0, 9.1 Hz, 1H), 4.14 (t, J=9.1 Hz, 1H), 4.74-4.78 (m, 1H), 7.41 (dd, J=2.2, 8.8 Hz, 1H), 7.52 (dd, J=2.2, 14 Hz, 1H), 7.69 (t, J=8.5 Hz, 1H), 8.16 (t, J=5.8 Hz, 1H), 11.6 (s, 1H); mp 192-3; MS (m/z): [M+H]+=381.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[C:5]2[NH:18][C:19](=[O:24])[CH2:20][N:21]([CH3:23])[CH3:22].C(N(CC)CC)C.[C:32]([Si:34]([CH3:37])([CH3:36])[CH3:35])#[CH:33]>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:22][N:21]([CH3:23])[CH2:20][C:19]([NH:18][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:33]#[C:32][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:3]=2)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=1)=[O:24]
Reactant: C#C[Si](C)(C)C
Reactant: CN(C)CC(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(Br)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CC(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(C#C[Si](C)(C)C)cc12
Temperature: 60 °C

Procedure:
To a mixture of Example 282C (2.56 g, 6.44 mmol), bis(triphenylphosphine)palladium(II) chloride (0.225 g, 0.321 mmol), and copper(I) iodide (0.073 g, 0.383 mmol) was added triethylamine (20 mL, 144 mmol) followed by ethynyltrimethylsilane (0.760 g, 7.73 mmol). The reaction mixture was heated at about 60° C. for about 3 hours. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (20 mL) and brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate in dichloromethane (10%) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.69 (s, 1H), 8.08 (s, 1H), 8.04 (d, 1H, J=9.0), 7.62 (d, 1H, J=8.8), 3.21 (s, 2H), 2.30 (s, 6H), 1.61 (s, 9H), 0.23 (s, 9H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][C:13]([O:15]C)=[CH:14][C:6]=2[C:5]1=[O:17])[CH:2]=[CH2:3].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:6]=2[C:5]1=[O:17])[CH:2]=[CH2:3]
Reactant: C=CCN1CCCc2ccc(OC)cc2C1=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCN1CCCc2ccc(O)cc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
A solution of 2-allyl-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (1.10 g, 0.0047 mol) in CH2Cl2 (20 mL) was treated at 0° C. with BBr3 (1M in CH2Cl2, 9.50 mL), and the resulting mixture stirred at 0° C. for 30 minutes. The solution was poured over ice, NaHCO3 was added, and the solution was extracted with CH2Cl2. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo to yield ca. 1.0 g (100%) of 2-allyl-8-hydroxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one as a colorless oil; 1H NMR(CDCl3) d8.2(brs, 1H), 7.47(s, 1H), 6.95(d, J=6 Hz, 1H), 6.84(dd, J=3, 6 Hz, 1H), 5.89(m, 1H), 5.22(m, complex, 2H), 4.20(d, J= 6 Hz, 2H), 3.18(t, J=6 Hz, 2H), 2.66(t, J=6 Hz, 2H), 2.15(s, 1H), 1.96(m, 2H); 13C NMR(CDCl3) d171.65(CO), 156.01, 135.68, 133.27, 129.55, 128.46, 118.51, 118.05, 115.91, 53.46, 49.81, 45.83, 30.87, 29.76, 29.12.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4]O.[CH2:10](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)CO>>[CH2:4]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:2][OH:1])[CH3:10]
Reactant: OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)CO
Reactant: OCC(CO)(CO)CO
Product: CCC(CO)(CO)CO

Procedure:
pentaerythritol or dulcitol.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O[C@H:33]1[CH2:37][NH:36][C@H:35]([C:38](O)=O)[CH2:34]1>CS(C)=O.[Cu]I>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([N:36]5[CH2:37][CH2:33][CH2:34][C@H:35]5[CH2:38][N:36]5[CH2:37][CH2:33][CH2:34][CH2:35]5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCC[C@H]3CN3CCCC3)cc1OCC2
Temperature: 90 °C
Yield: 89.4 %

Procedure:
A mixture of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 95 from Example 95 (100 mg, 0.27 mmol), (S)-pyrrolidinylmethylpyrrolidine (206 mg, 1.34 mmol), K3PO4 (114 mg, 0.53 mmol), trans-4-hydroxyproline (14 mg, 0.11 mmol) and CuI (10 mg, 0.05 mmol) in DMSO (0.5 mL) was heated at 90° C. for 23 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was dissolved in DCM and washed with 10% citric acid, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-6% MeOH in DCM) then Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was freeze-dried from MeCN/H2O to afford 133 (22 mg, 19%) as a white solid. LCMS: RT 2.81 min [M+H]+ 448.4. 1H NMR (DMSO, 400 MHz): δ 8.19 (1H, d, J=8.93 Hz), 7.88 (1H, d, J=0.63 Hz), 7.77 (1H, s), 6.45 (1H, dd, J=9.00, 2.43 Hz), 6.13 (1H, d, J=2.38 Hz), 5.93-5.92 (1H, m), 4.48-4.36 (4H, m), 3.89-3.81 (1H, m), 3.42-3.35 (1H, m), 3.15-3.05 (1H, m), 2.64-2.57 (2H, m), 2.43-2.40 (4H, m), 2.00-1.98 (4H, m), 1.74-1.66 (4H, m), 1.47 (6H, d, J=6.61 Hz)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][CH2:10]2)=[O:5].C(O)(=O)C.[Br:20]Br>O>[CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[Br:20])[CH2:12][CH2:11][CH2:10]2)=[O:5]
Reactant: BrBr
Reactant: COCC(=O)Nc1ccc2c(c1)CCC2
Solvent: CC(=O)O
Solvent: O
Product: COCC(=O)Nc1cc2c(cc1Br)CCC2
Temperature: 10 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 5-methoxyacetamidoindan (5.50 g, 0.027 mol) and glacial acetic acid (25 ml) was cooled in an ice-water bath (˜10° C.). Bromine (1.5 ml, 0.029 mol) was then dropwise added over a 20 min period while the temperature was kept between 10-15° C. The reaction mixture was then stirred for a longer 1 hour and then it was poured into an ice-water bath (100 ml) with the aid of water (70 ml). The precipitate was collected by filtration, washed with plenty of water (150 ml) and dried in vacuo over P2O5 to afford the title compound (6.98 g, 91%), m.p. 84-86° C.; 1H-NMR (250 MHz, CDCl3, TMS) 2.09 (m, 2H, 2-CH2), 2.88 (m, 4H, 1-CH2 and 3-CH2), 3.55 (s, 3H, OCH3), 4.04 (s, 2H, 2-CH2OMe), 7.34, 8.22 (2×s, 2H, 4-H, 7-H), 8.83 (s, 1H, CONH);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[CH2:10](O)[CH2:11][CH2:12][OH:13]>C1(C)C=CC=CC=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:13][CH2:12][CH2:11][CH2:10][O:9]2)=[N:6][CH:7]=1
Reactant: OCCCO
Reactant: O=Cc1ccc(Br)cn1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCCO2)nc1
Yield: 101.9 %

Procedure:
To solution of 5-bromo-2-formylpyridine (10 g, 53.8 mmol), 1,3-propanediol (3.89 mL, 53.8 mmol) in toluene (30 mL) was added CSA (1.249 g, 5.38 mmol). The reaction mixture was heated to reflux for 4 h with a Dean-Stark trap. The reaction mixture was quenched by addition of saturated solution of sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford compound 278 (13.37 g, 54.8 mmol, 101% yield, crude) as a brown solid that was used in the next step with no additional purification. MS (m/z): 244.06-246.06 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+](=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N-].[OH-].[Na+]>C(Cl)Cl.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][O:16][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:12][CH:13]=2)[CH:2]=1
Reactant: OCCc1ccc(Cc2cccnc2)cc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)COCCc1ccc(Cc2cccnc2)cc1
Yield: 15.7 %

Procedure:
In 10 ml of methylene chloride was dissolved 1.0 g of 2-[4-(pyridin-3-ylmethyl)phenyl]ethanol, and 980 mg of p-toluene sulfonic acid monohydrate was added thereto with ice-cooling. To the resulting solution was added 2.7 g of ethyl diazoacetate with ice-cooling, after which 700 mg of boron trifluoridediethyl ether complex was dropped into the solution. The resulting mixture was subjected to reaction at the same temperature for one hour. Subsequently, 20 ml of water and 20 ml of methylene chloride were added to the reaction mixture, and the pH thereof was adjusted to 8 with 1N aqueous sodium hydroxide solution, after which the organic layer was separated, washed successively with 20 ml of water and 20 ml of a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: toluene:ethyl acetate (1:1 by volume)], to obtain 220 mg (yield 15.7%) of oily ethyl 2-[4-(pyridin-3-ylmethyl)phenyl]ethyloxyacetate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.O=[C:12]([C:18](OCC)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[N:9]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18](=[O:19])[NH:10]2
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1nc2cc(Cl)c(Cl)cc2[nH]c1=O

Procedure:
A solution of 17.7 g. of 4,5-dichloro-o-phenylenediamine in 200 ml. of anhydrous ethanol was prepared. A 17.4 g. batch of diethyl 2-ketomalonate were added to this solution and the mixture was heated to refluxing temperature for about 17 hours. The volatile constituents were removed by evaporation in vacuo. Recrystallization of the residue from ethanol yielded 20 g. of ethyl 6,7-dichloro-3,4-dihydro-3-oxo-2-quinoxaline carboxylate formed in the above reaction, melting in the range 226°-227° C.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH3:41])[C:19]2[O:25][C:24]3[C:26]([Cl:37])=[CH:27][C:28]([N:30]([CH2:34][CH2:35][OH:36])[CH2:31][CH2:32]O)=[CH:29][C:23]=3[CH2:22][S:21](=[O:39])(=[O:38])[C:20]=2[CH:40]=1)=[O:15].C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1.O>[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH3:41])[C:19]2[O:25][C:24]3[C:26]([Cl:37])=[CH:27][C:28]([N:30]4[CH2:31][CH2:32][O:36][CH2:35][CH2:34]4)=[CH:29][C:23]=3[CH2:22][S:21](=[O:38])(=[O:39])[C:20]=2[CH:40]=1)=[O:15]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCO)CCO)cc(Cl)c1O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCOCC3)cc(Cl)c1O2

Procedure:
Catalytic amount of p-toluene sulphonic acid (PTSA) was added to a stirred solution of compound of Example 13 (1 g, 2.19 mmol) in xylene (50 mL). Reaction mixture was refluxed in Dean-Stark apparatus for 6 h and xylene was removed by distillation. Reaction mixture was diluted with 50 mL water, neutralized using 10% sodium bicarbonate solution and extracted using ethyl acetate (3×50 mL), washed with brine (2×10 mL), dried on sodium sulphate. The crude product obtained was purified by column chromatography (silica gel, ethylacetate/pet. ether) to obtain the title compound. Yield: 0.32 g, (33%); mp: >320° C.; 1H NMR (DMSO-d6, 300 MHz): δ 2.68 (s, 3H, CH3), 3.15 (s, 4H, 2CH2), 3.74 (s, 4H, 2CH2), 3.90 (s, 3H, OCH3), 4.65 (s, 2H, CH2), 6.76 (s, 1H, Ar), 6.88 (s, 1H, Ar), 8.06 (s, 1H, Ar), 8.44 (s, 1H, Ar); MS: m/e (EI) 437 (M+).