Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([CH3:29])[C:6]([CH3:30])=[C:5]([O:31][CH3:32])[CH:4]=1.[F:33]/[C:34](=[CH:43]\[CH:44]=[C:45](/[CH3:48])\[CH:46]=O)/[C:35](/[CH3:42])=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38].C1OC1CC>CCOCC>[Cl:2][C:3]1[C:8](/[CH:9]=[CH:48]/[C:45](/[CH3:46])=[CH:44]/[CH:43]=[C:34](\[F:33])/[C:35](/[CH3:42])=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:7]([CH3:29])[C:6]([CH3:30])=[C:5]([O:31][CH3:32])[CH:4]=1
Reactant: COc1cc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Reactant: CCOC(=O)/C=C(C)/C(F)=C/C=C(\C)C=O
Agent: CCC1CO1
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)/C=C(C)/C(F)=C/C=C(C)/C=C/c1c(Cl)cc(OC)c(C)c1C
Yield: 35 %

Procedure:
A mixture of 6.0 g. (12.46 mmol) of 6-chloro-4-methoxy-2,3-dimethylbenzyl triphenylphosphonium chloride and 2.71 g. of ethyl (E,Z,E)-4-fluoro-3,7-dimethyl-8-oxo-2,4,6-octatrienoate in 15 ml. of 1,2-butylene oxide was heated at 110° C. in a sealed tube for 60 hours. The resulting mixture was worked up with ether in the usual manner to give 13.53 g. of crude product. This material was chromatographed on 300 g. of silica gel. Elution with 1:4 ether-petroleum ether yielded 4.65 g. of yellow crystals. Recrystallization of this material from methylene chloride-petroleum ether afforded 1.67 g. (35% yield) of pure ethyl (E,Z,E,E)-9-(6-chloro-4-methoxy-2,3-dimethylphenyl)-4-fluoro-3,7-dimethyl-2,4,6,8-nonatetraenoate as yellow crystals, mp. 126°-128° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1.N>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:20]=2)=[CH:15][CH:14]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: ON=C(Cl)c1cncc(F)c1
Agent: N
Product: Fc1cncc(-c2cc(-c3ccc(Cl)cc3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 1-chloro-4-ethynylbenzene (Aldrich, 68 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.42 (s, 1H), 7.57 (dt, J=8.9, 2.3 Hz, 2H), 7.92 (dt, J=8.9, 2.3 Hz, 2H), 8.17 (ddd, J=9.3, 2.8, 1.8 Hz, 1H), 8.61 (d, J=2.8 Hz, 1H), 8.96 (t, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 277 (M+H)+, 275 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=[C:8]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:9]=1.[CH:24]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]1[S:30]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=[C:8]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:9]=1)(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: CCOC(=O)CCc1cc(CCN)cc(Cc2cccnc2)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(CCNS(=O)(=O)C2CCCCC2)cc(Cc2cccnc2)c1
Yield: 45.5 %

Procedure:
A solution of ethyl 3-[3-(2-aminoethyl)-5-(3-pyridylmethyl)phenyl]propanoate (Preparation 47; 0.60 g), cyclohexylsulphonyl chloride (0.526 g), triethylamine (0.194 g) and 4-dimethylaminopyridine (0.352 g) in dichloromethane (6 ml) was stirred at room temperature for 3 hours and then washed with water and dried (MgSO4). Evaporation under vacuum of the solvent gave a gum which was chromatographed on silica gel. Elution with dichloromethane, followed by a dichloromethane:methanol (97:3) mixture gave the title compound as a gum (401 mg); Rf 0.70 (SS 2); δ (CDCl3): 1.10-1.25(2H,m), 1.21(3H,t,J=7.1 Hz), 1.37-1.50(2H,m), 1.65-1.70(2H,m), 1.83-1.86(2H,m), 2.05-2.09(2H,m), 2.57(2H,t,J=7.7 Hz), 2.79(2H,t,J=6.9 Hz), 2.88 (2H,t,J=7.7 Hz), 3.30-3.37(2H,m), 3.91(2H,s), 3.99-4.02 (1H,m), 4.10(2H,q,J=7.1 Hz), 6.86(1H,s), 6.89(1H,s), 6.91(1H,s), 7.21-7.23(1H,m), 7.44(1H,d,J=7.9 Hz), 8.45-8.47(2H,m).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][O:21][C:3]=12.[CH2:22]([O:29][CH:30]1[CH2:33][CH:32]([S:34](Cl)(=[O:36])=[O:35])[CH2:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:34]([CH:32]2[CH2:33][CH:30]([O:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:31]2)(=[O:36])=[O:35])=[C:3]2[O:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Reactant: O=S(=O)(Cl)C1CC(OCc2ccccc2)C1
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(OCc3ccccc3)C2)c2n(c1=O)CCO2
Yield: 31.2 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 7A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 0.53 g, 1.0 mmol) in pyridine (4 mL) was reacted with 3-benzyloxy-cyclobutanesulfonyl chloride (0.179 mg, 1.2 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in DCM) afforded 195 mg of the product (23.8% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[S:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][NH:23][C@@H:24]([CH2:35][CH2:36][C:37]2[NH:38][CH:39]=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:41]=2)[C:25](OCC2C=CC=CC=2)=[O:26])=[CH:14]1.C(N(CC)CC)C>C1COCC1>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][N:23]2[C@@H:24]([CH2:35][CH2:36][C:37]3[NH:38][CH:39]=[C:40]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[N:41]=3)[C:25](=[O:26])[N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[C:11]2=[S:12])=[CH:14]1
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Reactant: O=C(OCc1ccccc1)[C@H](CCc1nc(-c2ccccc2)c[nH]1)NCc1c[nH]c2ccccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1[C@H](CCc2nc(-c3ccccc3)c[nH]2)N(Cc2c[nH]c3ccccc23)C(=S)N1c1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
4-nitro-phenylisothiocyanate (43 mg; 1.2 eq.) is added to a solution of benzyl (2S)-2-[(1H-indol-3ylmethyl)amino]-4(4-phenyl-1H-imidazol-2-yl)butanoate (93 mg; 1 eq.) in THF (2 ml). The mixture is stirred for 2 hours at approximately 20° C. then diluted with 4 ml of THF. Aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added, then triethylamine (200 μl). The mixture is stirred for 15 hours at approximately 20° C. then filtered on frit. The filtrate is concentrated to dryness under reduced pressure at 40° C. (a co-evaporation with dichloromethane is necessary to eliminate the excess triethylamine). Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate/heptane 9:1) yields the expected compound (90 mg; 84% yield).
Reaction SMILES: O[CH2:2][N:3]1[CH2:7][CH2:6][N:5]([CH2:8]O)[C:4]1=[O:10].[C:11]([C:15]1[CH:16]=[C:17]([SH:26])[CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])([CH3:14])([CH3:13])[CH3:12].Cl>CO>[C:11]([C:15]1[CH:16]=[C:17]([S:26][CH2:2][N:3]2[CH2:7][CH2:6][N:5]([CH2:8][S:26][C:17]3[CH:16]=[C:15]([C:11]([CH3:12])([CH3:13])[CH3:14])[C:20]([OH:21])=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=3)[C:4]2=[O:10])[CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C1N(CO)CCN1CO
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(SCN2CCN(CSc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C2=O)cc(C(C)(C)C)c1O
Yield: 78 %

Procedure:
A solution of 3.65 grams of 1,3-bis(hydroxymethyl)-2-imidazolidone and 11.92 grams of 3,5-di-t-butyl-4-hydroxybenzenethiol in 100 ml of methyl alcohol was treated with anhydrous hydrogen chloride. The reaction mixture was cooled and the product recrystallized from methyl alcohol to give 11.43 grams of white solid, m.p. 173°-176° C.
Reaction SMILES: [C:1]([N:5]1[CH2:26][CH2:25][CH2:24][C:8]2[C:9]([Br:23])=[C:10]3[C:19]4[CH:18]=[C:17](Br)[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C([O-])([O-])=O.[K+].[K+]>C(COC)OC.O.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>[C:1]([N:5]1[CH2:26][CH2:25][CH2:24][C:8]2[C:9]([Br:23])=[C:10]3[C:19]4[CH:18]=[C:17]([C:30]5[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=5)[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(cc1Br)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Reactant: OB(O)c1cccnc1
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: COc1cc2c(cc1-c1cccnc1)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Temperature: 90 °C
Yield: 63.6 %

Procedure:
A mixture of 150 mg of 13c, 44 mg of pyridine-3-boronic acid, 80 mg of K2CO3 and 22 mg of Pd(PPh3)4 in 3 ml of degassed dimethoxyethane was heated at 90° C., for 16 hr. The reaction mixture was cooled and diluted with 20 ml of water and the product was extracted with ethyl acetate. The extract was washed once with 2N KOH and once with water, dried and concentrated. The crude material was chromatographed over silica gel, using a gradient of heptane/ethyl acetate as eluent. The product isolated was triturated with pentane, to provide 95 mg of 13d as white, crystalline material. Mp 184-186° C. Rf 0.25 (heptane/ethyl acetate 1/1). MS-ESI: [M+1] 494.11 and 496.11.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[C:26]([CH3:27])=[N:25][C:24]2[C:19](=[CH:20][C:21]([F:29])=[C:22]([F:28])[CH:23]=2)[N:18]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:17]1[C:26]([CH3:27])=[N:25][C:24]2[C:19](=[CH:20][C:21]([F:29])=[C:22]([F:28])[CH:23]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Reactant: Cc1nc2cc(F)c(F)cc2nc1Cl
Solvent: CN(C)C=O
Product: Cc1nc2cc(F)c(F)cc2nc1NC[C@@H]1CCCCN1C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
(S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.14 g), and 2-chloro-6,7-difluoro-3-methylquinoxaline Teng et al PCT Int. Appl (2000), WO00/42026A1 20000720 (1.14 g) were dissolved in DMF (2 ml) and heated to 90° C. for 3 days under an atmosphere of argon. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated brine, dried and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 10 to 50% ethyl acetate in hexane. The title compound was obtained as a pink foam (0.524 g), MH+ 393.
Reaction SMILES: CN(C)C(=O)C.[I-].[CH3:8][N+:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:21])=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]=1.CC(C)([O-])C.[K+]>O>[CH3:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:21])=[C:14]([O:19][CH3:20])[CH:15]=2)[CH2:10]1
Reactant: COc1cc2c(cc1O)C=[N+](C)CC2
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc2c(cc1O)CN(C)CC2
Reaction time: 0.08 h

Procedure:
2,3',4'-Trimethoxy-5-methyl-4-nitrodiphenyl ether (2e) (6.38 g) was added to N,N-dimethyl acetamide (125 ml) under nitrogen, stirred for 5 min., and treated with 2 -methyl-6-methoxy-7-hydroxy-3,4-dihydroisoquinolinium iodide (1) (7.65 g). Potassium t-butoxide (4.39 g) was then added in small portions over 15 min. The reaction mixture was stirred under nitrogen at room temperature for 7 hours, diluted with cold water (600 ml), stirred for 10-15 min. and refrigerated overnight. The supernatant aqueous layer was decanted from the solid which was collected and washed with 1:1 methanol-ether (20 ml) followed by ether (100 ml) and sucked dry (9.40 g, 92%), to yield 1-[2'-nitro-4'-methoxy-5'-(3", 4"-dimethoxy)phenoxybenzyl]-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline (3e), mp 169°-171°. An analytical sample was crystallized from chloroform-methanol: mp 173°-174°; nmr δ 2.40 (3H, NCH3), 3.85, 3.88, 3.92, and 3.98 (each 3H, 4 OCH3), 6.37-7.60 (7H, ArH).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][S:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([CH2:24][NH2:25])[CH:21]=[CH:20][C:18]=2[N:19]=1>CN(C=O)C.CCOC(C)=O>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH:25][CH2:24][C:22]2[CH:21]=[CH:20][C:18]3[N:19]=[C:15]([S:14][CH3:13])[S:16][C:17]=3[CH:23]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CSc1nc2ccc(CN)cc2s1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])c(NCc2ccc3nc(SC)sc3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a solution of 2-chloro-6-methoxy-3-nitropyridine (430 mg, 2.3 mmol) in DMF (6 mL) was added (2-(methylthio)benzo[d]thiazol-6-yl)methanamine (437 mg, 2.1 mmol) from Step 4 of this Example slowly at 0° C. The reaction mixture was stirred at rt overnight. The resulting reaction mixture was diluted with 60 mL of EtOAc and washed with saturated aq NaHCO3 and brine. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using CH2Cl2 as eluent to give 6-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-amine as a yellow solid (431 mg, 57%). LCMS (ESI) m/z 363 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[OH:15][CH:16]1[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)([O:22][CH3:23])[CH2:20][CH2:19][O:18][CH2:17]1>>[CH3:13][N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][O:30][C:26]3[CH:25]=[C:24]([C:21]4([O:22][CH3:23])[CH2:20][CH2:19][O:18][CH2:17][CH:16]4[OH:15])[CH:29]=[CH:28][CH:27]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14]
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Reactant: COC1(c2cccc(O)c2)CCOCC1O
Product: COC1(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCOCC1O
Yield: 84 %

Procedure:
Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one was reacted with (3RS,4SR)-3-hydroxy-4-(3-hydroxyphenyl)-4-methoxytetrahydropyran to give (3RS,4SR)-4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)phenyl]-3-hydroxy-4-methoxytetrahydropyran in 84% yield, m.p. 62°-66° C.
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[CH:3][C:2]=1[CH3:9].[CH2:10]([O:17][CH2:18][CH2:19]Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1>[CH2:10]([O:17][CH2:18][CH2:19][CH2:8][C:4]1[CH:5]=[C:6]([CH3:7])[N:1]=[C:2]([CH3:9])[CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCCOCc1ccccc1
Reactant: Cc1cc(C)nc(C)c1
Solvent: C1CCOC1
Product: Cc1cc(CCCOCc2ccccc2)cc(C)n1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Collidine (1), (5 g, 41.3 mmol) in dry tetrahydrofuran was added dropwise and the mixture was stirred for 60 min at -40° C. To this stirred mixture 1-benzoxy-2-bromethane (Tetrahedron Lett. 28, 2639-42, 1979) (8.24 g, 39.2 mmol) dissolved in dry tetrahydrofuran (20 ml) was added dropwise during 30 min and the reaction mixture was stirred overnight.
Reaction SMILES: C(N(CC)CC)C.[Cl-].[CH2:9]([NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1I)[CH:10]=[CH2:11]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:21])[NH:12][CH:9]=1
Reactant: C=CCNC(=O)c1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c[nH]c(=O)c2ccccc12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Under an N2 atmosphere, 985 ml (7.07 mol) of triethylamine, 892 g (3.21 mol) of tetra-nbutylammonium chloride and 12.77 g (57 mmol) of Pd(OAc)2 are added to 815 g (2.8 mol) of 2-iodo-benzoic acid allylamide in 4.5 l of DMF, and heated to 100° C. After 4 h, cooling is effected to RT, and the mixture is partially concentrated by evaporation on a RE. The residue is partitioned between 5 l of water and 5 l of EtOAc, the water phase is separated and extracted twice with EtOAc. The organic phases are washed with water, 0.1 N HCl, water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2, EtOAc/toluene 1:1) and crystallisation from toluene yields 4-methyl-2H-isoquinolin-1-one; m.p. 175-176° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:9]([CH2:10][CH2:11][C:12]3[C:13]4[C@:21]([CH3:29])([CH2:22][CH2:23][C:24]=32)[C@@H:16]([C@H:17]([CH3:20])[CH2:18][OH:19])[CH2:15][CH:14]=4)[C:8]1([CH3:31])[CH3:30])[CH3:5])[CH3:2].[CH3:32][C:33]([CH3:36])([O-])[CH3:34].[K+].C1OCCOCCOCCOCCOCCOC1.ClCC(C)=C>O.C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@H:9]([CH2:10][CH2:11][C:12]3[C:13]4[C@:21]([CH3:29])([CH2:22][CH2:23][C:24]=32)[C@@H:16]([C@H:17]([CH3:20])[CH2:18][O:19][CH2:34][C:33]([CH3:36])=[CH2:32])[CH2:15][CH:14]=4)[C:8]1([CH3:31])[CH3:30])[CH3:5])[CH3:2]
Reactant: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@H](C)CO)[C@@]1(C)CC3
Reactant: CC(C)(C)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C=C(C)CCl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)COC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(C)OCC)C(C)(C)[C@@H]1CC3
Temperature: 70 °C
Yield: 107.5 %

Procedure:
vii)—A mixture of (3β,5α,20S)-3-[(1-ethoxyethyl)oxy]-4,4,20-trimethylpregna-8,14-dien-21-ol (1.0 g), dry toluene (67 ml), potassium t-butoxide (3.34 g), 18-crown-6 (0.581 g) and 3-chloro-2-methyl-1-propene (1.14 ml) was heated at 70° C. for 1.5 h. After cooling, the reaction mixture was poured into water and the product extracted into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (3β,5α,20S)-3-[(1-ethoxyethyl)oxy]-4,4-dimethyl-23-oxacholesta-8,14,25-triene (1.21 g), which was used in the following step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15]Cl)[CH:6]=[C:5]2[CH:17]=[O:18].[C:19]([O-:22])(=[O:21])[CH3:20].[Na+]>CS(C)=O.O>[C:19]([O:22][CH2:15][CH2:14][CH2:13][N:7]1[CH:6]=[C:5]([CH:17]=[O:18])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[C:8]1=[O:12])(=[O:21])[CH3:20]
Reactant: O=Cc1cn(CCCCl)c(=O)c2ccc(Br)cc12
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)OCCCn1cc(C=O)c2cc(Br)ccc2c1=O
Temperature: 70 °C
Reaction time: 10 h

Procedure:
A solution of 6-bromo-2-(3-chloropropyl)-1-oxo-1,2-dihydroisoquinoline-4-carbaldehyde (Example 10b, 0.90 g) in DMSO (10 mL) was treated with sodium acetate (0.45 g) under nitrogen. The resulting mixture was stirred at 70° C. for 10 h. The cooled reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (250 mL). The organic was dried (MgSO4), filtered and evaporated to afford subtitle compound. (0.91 g).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[O:5][C:4](=[O:26])[CH:3]=1.[C:27]([C:31]1[CH:36]=[C:35]([O:37][CH2:38][CH2:39][O:40][Si](C(C)(C)C)(C)C)[C:34]([CH3:48])=[CH:33][C:32]=1[S:49]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CO.Cl>[C:27]([C:31]1[CH:36]=[C:35]([O:37][CH2:38][CH2:39][OH:40])[C:34]([CH3:48])=[CH:33][C:32]=1[S:49][C:3]1[C:4](=[O:26])[O:5][C:6]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[CH2:7][C:2]=1[OH:1])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(CCc2ccc(O)cc2)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OCCO[Si](C)(C)C(C)(C)C)cc2C(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(CCc3ccc(O)cc3)OC2=O)c(C(C)(C)C)cc1OCCO

Procedure:
The title compound was synthesized using General Method 9 using 0.07 g (2 mmol) of 4-hydroxy-6,6-bis-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example PP), 1.00 g (2 mmol) of toluene-4-thiosulfonic acid S-{2-tert-butyl-4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-methyl-phenyl} ester (prepared in Example PPP), 1.06 g (8 mmol) K2CO3, and DMF (5 mL). The solid which was obtained was then dissolved in 20 mL MeOH and 2 mL of 1N HCl. After 15 minutes the reaction was concentrated and the residue partitioned between EtOAc and H2O; the organic layer was separated, dried (Na2SO4) and concentrated. Trituration with Et2O yielded the title compound, m.p. 106°-107° C. 1H NMR (DMSO-d6) δ 1.49 (s, 9 H), 1.75 (s, 3 H), 2.0 (t, 4 H), 2.5 (t, 4 H), 3.4 (dd, 2 H), 3.7 (bs, 2 H), 3.95 (t, 2 H), 4.8 (br s, 1 H), 6.66 (d, 4 H), 6.7 (s, 1 H), 6.8 (s, 1 H), 6.98 (d, 4 H), 9.17 (s, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].C1COCC1.C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:21](=[O:22])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][C:3]=1[F:9]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(Br)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Br)c(F)c1)OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a 12-L, three-neck, round-bottom flask equipped with an overhead stirrer, nitrogen inlet/outlet, addition funnel and thermocouple was charged 4-bromo-3-fluoroaniline (800.0 g, 4.21 mol, Matrix lot #Q13H), THF (6.4 L, 8 vol), and solid sodium bicarbonate (530.5 g, 6.32 mol, 1.5 eq). The addition funnel was charged with benzyl chloroformate (861.9 g, 5.05 mol, 1.2 eq), which was added dropwise to the reactor over 70 minutes. The temperature of the reaction was maintained below 20° C. with an ice water bath. The batch was aged 1 hour at room temperature at which point HPLC analysis indicated that the reaction was complete. The reaction mixture was transferred to a 22-L flask and the mixture was diluted with water (6.4 L, 8 vol). The two-phase mixture was warmed to 50° C. and held at temperature for 16 hours to quench the excess benzyl chloroformate. The mixture was transferred hot to a separatory funnel to remove the lower aqueous phase. A rag layer was observed which was taken with the aqueous layer. The THF layer was filtered through Whatman #1 filter paper to remove some particulates, and the mixture was transferred back to a 22-L flask equipped for distillation. Heptane was added in portions and distilled to remove the THF. (Note that it is best to distill some of the THF out first before adding the first amount of heptane.) A total of 26.5 L of heptane was added, and the total distillate collected was 25 L. At this point, the pot temperature had reached 97.7° C. and the distillate coming over contained 0.9% THF by 1H NMR analysis. The mixture was cooled to room temperature and the thick white slurry was filtered. The filter cake was washed with heptane (4 L). The product was dried in a vacuum oven at 40° C. to give 1257.0 g of intermediate 5 (92% yield). The HPLC assay was 98.3% (AUC).