Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:32]3[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]3)=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:32]3[CH2:37][CH2:36][CH:35]([NH:38][CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]4=[O:16])[CH2:34][CH2:33]3)=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1
Reactant: NC1CCN(Cc2ccc3c(c2)OCCO3)CC1
Reactant: COC(=O)c1cc(=O)n(CC=O)c2cc(OC)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(=O)n(CCNC2CCN(Cc3ccc4c(c3)OCCO4)CC2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To 10 mL of a chloroform solution containing 111 mg of methyl 7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxylate and 93 mg of 1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-4-ylamine, 23 μL of acetic acid was added and stirred at room temperature for 1 hour. To the reaction mixture, 132 mg of sodium triacetoxyborohydride was added and stirred for 0.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane=3:1], to give 134 mg of methyl 1-(2-(1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-4-ylamino)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].Br[CH2:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:23]=2[N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:29][C:26]1[CH:27]=[CH:28][C:22]2[S:21][C:20]([CH2:19][N:4]3[C:5](=[O:16])[C:6]4[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=4[N:2]([CH3:1])[C:3]3=[O:17])=[N:24][C:23]=2[CH:25]=1
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: Clc1ccc2sc(CBr)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc3cc(Cl)ccc3s1)c(=O)n2C
Yield: 96.1 %

Procedure:
By utilizing the well known method, 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 1a (297 mg, 1 mmol) was dissolved in N,N-dimethylformamide (8 ml). 2-bromomethyl-5-chloro-1,3-benzothiazole (263 mg, 1 mmol) and potassium carbonate (213 mg, 1.5 mmol) were added to give a reaction mixture. The reaction mixture was reacted overnight at room temperature and TLC was used to monitor the reaction progress. After the reaction was completed, the obtained reaction mixture was poured into water, suction filtered, and the obtained solid was washed with water, dried to give 1-[(5-chloro-1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 3b (460 mg, light yellow solid), yield: 96%.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[CH:12]([CH:15]([CH3:17])[CH3:16])[N:11]([CH3:18])[S:10]2(=[O:20])=[O:19])C=CC=CC=1.S(Cl)([Cl:24])(=O)=O>C(Cl)Cl>[Cl:24][CH2:8][N:9]1[C:13](=[O:14])[CH:12]([CH:15]([CH3:17])[CH3:16])[N:11]([CH3:18])[S:10]1(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)C1C(=O)N(CSc2ccccc2)S(=O)(=O)N1C
Solvent: ClCCl
Product: CC(C)C1C(=O)N(CCl)S(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 2-phenylthiomethyl-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (6.38 g, 23.31 mmol) in 150 ml of methylene chloride was added sulfuryl chloride (2.5 ml, 30.4 mmol) and the mixture was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo and the residue triturated in hexane to afford 4.32 g (88%) of 2-chloromethyl-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula II: R1 =H; R2 =isopropyl; R3 =CH3 ; X=Cl) as a solid, m.p. 118.5°-119.5° C.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:13][CH2:12][O:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[CH2:14]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]1)[CH3:15]>>[CH2:14]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH:22]([CH2:12][CH2:13][CH:10]([OH:11])[C@H:7]2[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]2)[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:18][CH2:17]1)[CH3:15]
Reactant: CCC[C@H]1CC[C@H](C2CCO2)CC1
Reactant: CC[C@H]1CC[C@H](CC(=O)OC(C)(C)C)CC1
Product: CCC[C@H]1CC[C@H](C(O)CCC(C(=O)OC(C)(C)C)[C@H]2CC[C@H](CC)CC2)CC1

Procedure:
Reaction operations were carried out according to the first step of Example 1 by using 1-(trans-4-propylcyclohexyl)oxetane (37) (3.1 g, 17.0 mmol) and tert-butyl 2-(trans-4-ethylcyclohexyl)acetate (40) (12.3 g, 54.4 mmol) as starting materials to obtain tert-butyl 2-(trans-4-ethylcyclohexyl)-5-hydroxy-5-(trans-4-propylcyclohexyl)pentanoate (41) (6.8 g, 14.5 mmol). The yield based on the compound (37) was 85%.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([CH3:15])=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].[H][H]>[Ni].N>[CH3:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([CH3:15])=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6]
Reactant: COc1c(C)cc(CC#N)c(C)c1OC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: COc1c(C)cc(CCN)c(C)c1OC

Procedure:
A mixture of 18.3 g (0.0865 mole) of the nitrile, 1.6 g of Raney nickel catalyst and 170 ml of saturated anhydrous methanolic ammonia is hydrogenated at 50°, 100 p.s.i. of hydrogen gas until hydrogen uptake stopped (about 6 hours). Removal of the catalyst by filtration followed by evaporation gives the 2-(2,5-dimethyl-3,4-dimethoxyphenyl)ethylamine which can be used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37](O[C:40](=[O:41])[C:30]=2[CH:29]=1)=[O:38]>C1C(O)=CC=CC=1C>[C:34]([C:33]1[CH:32]=[C:31]2[C:37](=[O:38])[N:1]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4([C:21]5[CH:22]=[CH:23][C:24]([N:27]6[C:37](=[O:38])[C:31]7=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:28][CH:29]=[C:30]7[C:40]6=[O:41])=[CH:25][CH:26]=5)[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=5[C:15]5[C:20]4=[CH:19][CH:18]=[CH:17][CH:16]=5)=[CH:6][CH:7]=3)[C:40](=[O:41])[C:30]2=[CH:29][CH:28]=1)([OH:36])=[O:35]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: Nc1ccc(C2(c3ccc(N)cc3)c3ccccc3-c3ccccc32)cc1
Solvent: Cc1cccc(O)c1
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1ccc(C3(c4ccc(N5C(=O)c6ccc(C(=O)O)cc6C5=O)cc4)c4ccccc4-c4ccccc43)cc1)C2=O
Reaction time: 16 h
Yield: 88.6 %

Procedure:
To a stirred mixture of 9,9-bis(4-aminophenyl)fluorene (13.9 g, 40 mmol) and 80 ml of m-cresol was added 1,2,4-benzenetricarboxylic anhydride (16.1 g, 84 mmol) over two minutes. The resulting mixture was stirred under gentle reflux (163°-170° C.) for three hours and then at ambient temperature for 16 hours. A pale yellow precipitate was filtered, washed with methanol, washed with toluene, and then dried in a vacuum oven at 100°-105° C. for 16 hours to provide the title compound as a pale yellow powder (24.7 g, 88.7% yield) that had a melting point of 328°-331° C. and a 1H NMR spectrum (DMSO d6) corresponding to δ8.39 (d,2H), 8.29 (br s, 2H), 8.05 (d, 2H), 8.00 (d, 2H), 7.61 (d, 2H), and 7.40 (m, 12H).
Reaction SMILES: [CH:1]([N:4]([CH3:22])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[C@H:7]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:6]1)([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CCN(CC)CC.[N:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH2:60][C:61](O)=[O:62])[CH:54]=1>C(Cl)Cl>[CH:1]([N:4]([CH3:22])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:61](=[O:62])[CH2:60][CH2:59][C:55]2[CH:54]=[N:53][CH:58]=[CH:57][CH:56]=2)[C@H:7]([CH2:12][S:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:14])=[O:15])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: O=C(O)CCc1cccnc1
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)CCc2cccnc2)[C@H](CS(=O)(=O)c2ccccc2)C1
Yield: 63.9 %

Procedure:
A solution of (1R,3R,4S)—N1-isopropyl-N1-methyl-3-(phenylsulfonylmethyl)-cyclohexane-1,4-diamine (see 30b) (50 mg, 0.154 mmol), 1-(3-Dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (EDCI) (32 mg, 0.166 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (22 mg, 0.166 mmol), Et3N (17 mg, 0.166 mmol) and 3-(pyridin-3-yl)propanoic acid (26 mg, 0.166 mmol) in CH2Cl2 (5 mL) was stirred overnight at room temperature. The mixture was dilute with CH2Cl2 (20 mL) and washed with water, brine and evaporated. The residue was chromatographed on silica gel (4-6% NH4OH/MeOH/CH2Cl2) to give the product (45 mg, 66%). MS found: (M+1)+: 458.53.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:24][C:25]([F:28])([F:27])[F:26])[C:19]=2[F:23])[CH:14]=1.C1(C)C=CC=CC=1.O>CN(C)C=O.[Cu](I)I.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>[F:23][C:19]1[C:20]2[C:15](=[CH:14][C:13]([C:11]#[C:10][C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)=[CH:22][CH:21]=2)[CH:16]=[CH:17][C:18]=1[O:24][C:25]([F:28])([F:27])[F:26]
Reactant: C#Cc1ccc(CCC)cc1
Reactant: Fc1c(OC(F)(F)F)ccc2cc(Br)ccc12
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCc1ccc(C#Cc2ccc3c(F)c(OC(F)(F)F)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.6 %

Procedure:
10 g of 4-propyl-1-ethynylbenzene and 19.5 g of 2-bromo-5-fluoro-6-trifluoromethoxynaphthalene were dissolved in 50 ml of N,N-dimethylformamide (DMF). To the solution were then added 50 mg of copper iodide (I) and 100 mg of tetrakis(triphenylphosphine)palladium (0). The reaction mixture was then stirred at room temperature for 5 hours. To the reaction solution was then added toluene. Insoluble matters water removed by filtration. The residue was then washed with water and saturated brine. The solvent was then distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate 9/1), and then recrystallized from ethanol to obtain 8.6 g of 1-fluoro-2-trifluoromethoxy-6-[(4-propylphenyl)ethynyl]naphthalene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([CH2:12][CH:13]([C:22]1[C:26]([CH:27]2[CH2:29][CH2:28]2)=[C:25]([CH:30]2[CH2:33][CH:32]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:31]2)[O:24][N:23]=1)[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[O:11].C1(C)C=CC=CC=1.FC(F)(F)C(O)=O.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([CH2:12][CH:13]([C:22]1[C:26]([CH:27]2[CH2:28][CH2:29]2)=[C:25]([CH:30]2[CH2:31][CH:32]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:33]2)[O:24][N:23]=1)[CH2:14][C:15]([OH:17])=[O:16])=[O:11]
Reactant: Cc1ccc(Cl)c(NC(=O)CC(CC(=O)OC(C)(C)C)c2noc(C3CC(CC(C)C)C3)c2C2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccc(Cl)c(NC(=O)CC(CC(=O)O)c2noc(C3CC(CC(C)C)C3)c2C2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
tert-Butyl 4-(2-Chloro-5-methylphenylcarbamoyl)-3-[4-cyclopropyl-5-(3-isobutylcyclobutyl)isoxazol-3-yl]butanoate (1.09 g) and toluene (3.2 mL) were mixed. To the mixture was added trifluoroacetic acid (3.2 mL) at ice temperature and the mixture was stirred at RT for 30 min. After water (5 mL) was poured into the reaction mixture dropwise at ice temperature, aqueous 4 N sodium hydroxide was added to the mixture dropwise and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/5→1/3→1/2→2/1→methanol/chloroform=1/8) to give the title compound (905 mg). The title compound was analyzed using a chiral column. The retention time of the title compound was 6.6 min., and the optical purity thereof was 94.8% ee.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][N:4]=1.[CH3:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH2:25][S:26][CH2:27][CH2:28][NH2:29]>>[CH3:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH2:25][S:26][CH2:27][CH2:28][NH:29][C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][N:4]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: COc1cccc(Cc2nnc(SC)[nH]c2=O)c1
Product: COc1cccc(Cc2nnc(NCCSCc3nc[nH]c3C)[nH]c2=O)c1
Reaction time: 0.08 h
Yield: 41.4 %

Procedure:
3-Methylthio-6-(3-methoxybenzyl)-1,2,4-triazin-5-one (1.07 g) and 2-(5-methyl-4-imidazolylmethylthio)ethylamine (0.77 g) were heated together on an oil bath (160°-70° ) for 3/4 hour. The solidified mass was broken up under methanol (ca 15 ml) and boiled for 5 minutes. After cooling the white solid was filtered off and recrystallised from dimethylformamide to give the title compound as a colourless solid (0.65 g) m.p. 203°-4°.
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36](Br)=[N:35][CH:34]=1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[CH:58][CH:57]=2)[C:52](=[O:63])[CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].C(N(C(C)C)C(C)C)C>CC(O)C>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:57]=[CH:58][C:59]([NH:62][C:36]3[C:37]4[N:38]([N:39]=[CH:40][N:41]=4)[C:33]([Br:32])=[CH:34][N:35]=3)=[CH:60][CH:61]=2)[C:52](=[O:63])[CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)C(=O)C1
Reactant: Brc1ncc(Br)n2ncnc12
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)C(=O)C1
Yield: 51.6 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 1, using 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (0.283 g, 1.00 mmol), 4-(4-amino-phenyl)-3-oxo-piperazine-1-carboxylic acid ter-t-butyl ester (0.300 g, 1.00 mmol) and N-ethyldiisopropyl-amine (0.20 mL, 1.02 mmol) in 2-propanol (1 mL). Purification of the crude material by silica gel column chromatography eluting with DCM followed by 98:2 DCM:MeOH affords 4-[4-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-phenyl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester as a white solid (0.252 g, 51%).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]#[N:5].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:4]#[N:5]
Reactant: CCCCCC(O)CC#N
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Product: CCCCCC(CC#N)OC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
A mixture of 3-hydroxycaprylonitrile (5.2 g., 36.8 millimole), dihydropyran (3.8 g., 45 millimole) and p-toluenesulfonic acid. hydrate (catalytic amount) is stirred at 25° C. for 16 hours, then diluted with ether (100 ml.). The resulting solution is washed with 5% aqueous sodium hydroxide (25 ml.) and water (2 × 25 ml.), dried over magnesium sulfate and filtered. Evaporation of the filtrate in vacuo affords the title compound as a pale yellow oil (7.9 g., 95%), pmr (CDCl 3) δ 0.93 (3H, t), 2.54 (2H, q) and 4.68 (H, m).
Reaction SMILES: C[O:2][C:3]1[C:4]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15]C(=O)C)[CH:9]=[CH:8][C:5]=2[O:6][CH:7]=1.O.OS(O)(=O)=O.[Na+].[Cl-]>O1CCCC1.C(OCC)(=O)C>[OH:15][CH2:14][CH2:13][O:12][C:10]1[CH:9]=[CH:8][C:5]2[O:6][CH2:7][C:3](=[O:2])[C:4]=2[CH:11]=1
Reactant: COc1coc2ccc(OCCOC(C)=O)cc12
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1COc2ccc(OCCO)cc21
Temperature: 25 °C

Procedure:
751 mg (7.0 mmol) XXII were stirred under reflux for 12 h in a mixture of 40 ml tetrahydrofuran, 20 ml water and 0.5 ml conc. H2SO4. Ethyl acetate and saturated NaCl solution were added to the reaction mixture cooled to room temperature. After separation of the phases, the aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over Na2SO4. After column filtration (50 g SiO2, n-hexane:ethyl acetate=1:1+1% acetic acid, applied with ethyl acetate), XXIII was obtained in a yield of 448 mg (2.3 mmol, 77%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[CH:27]([Si:30]([CH:50]([CH3:52])[CH3:51])([CH:47]([CH3:49])[CH3:48])[O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[S:42][C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[CH:39]=2)=[CH:34][CH:33]=1)([CH3:29])[CH3:28].C1COCC1>ClC(Cl)C.CN(C=O)C.Cl[Ti](Cl)(Cl)Cl>[CH:50]([Si:30]([CH:27]([CH3:29])[CH3:28])([CH:47]([CH3:49])[CH3:48])[O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[S:42][C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[C:39]=2[C:7]([C:6]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:4]([O:3][CH3:2])[CH:5]=2)=[O:9])=[CH:34][CH:33]=1)([CH3:52])[CH3:51]
Reactant: COc1cc(C(=O)O)ccc1OCCN1CCCC1
Reactant: CC(C)[Si](Oc1ccc(-c2cc3ccccc3s2)cc1)(C(C)C)C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2c(-c3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc3)sc3ccccc23)ccc1OCCN1CCCC1
Temperature: 25 °C

Procedure:
A slurry of 4.34 g (14.4 mmol) of 3-methoxy-4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride (Part G, below) in 75 mL of dichloroethane was treated with 2 drops of DMF followed by 5.00 mL (57.3 mmol; 4 eq) of oxalyl chloride. The reaction was stirred at ambient temperature until gas evolution ceased and was concentrated in vacuo. The solid was reconstituted in 75 mL dichloroethane. The mixture was cooled to 0° C., treated with 5.00 g (13.0 mmol; 0.9 eq) of 2-(4-triisopropylsilyloxyphenyl)benzo[b]thiophene (Part B) and 6.40 mL (58.4 mmol; 4 eq) of TiCl4, and stirred at ambient temperature for 5 h. The reaction was quenched by the addition of 50 mL of sat'd aq NaHCO3. The two layers were separated and the aqueous layer was extracted with EtOAc (4×25 mL). The combined organic layers were washed with H2O (50 mL), dried over K2CO3, filtered, and concentrated in vacuo to give an oil. Flash chromatography (SiO2; 15% THF and 5% TEA in hexanes) afforded 5.60 g (8.90 mmol; 62%) of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20]Cl)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:22].[Li+]>C1COCC1>[Br:22][CH2:20][C:15]1[C:12]2[CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10][C:11]=2[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Reactant: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CBr)c2CC1
Yield: 85.2 %

Procedure:
Combine 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.17 g, 8.14 mmol) and lithium bromide (0.98 g, 11.3 mmol) in anhydrous THF (60 mL) and stir at room temperature for 1 h. Concentrate in vacuo and partition the residue between dichloromethane/water. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 10:1) to obtain the title compound as a white solid (2.6 g, 85%). MS (APCI+) m/z: 274 (M-Boc+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[N+:16]([O-])=O)[CH2:2][CH2:3][CH3:4].[C:19](O)(=O)[CH2:20][OH:21]>>[CH2:1]([N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:19]1[CH2:20][OH:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1c([N+](=O)[O-])cnc2ccccc12
Reactant: O=C(O)CO
Product: CCCCn1c(CO)nc2cnc3ccccc3c21
Yield: 78.3 %

Procedure:
Using the general method of Example 1, N-butyl-3-nitro-4-quinolinamine (9.8 g, 0.04 mole, Example 122) was hydrogenated then reacted with glycolic acid (9.1 g, 0.12 mole) to provide 8.0 g of the desired product as a solid. A small sample was recrystallized from ethyl acetate to provide pure material, m.p. 146°-149° C. Analysis: Calculated: % C, 70.6; % H, 6.7; % N, 16.5; Found: % C, 70.3; % H, 6.7; % N, 16.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[C:13]([NH:19][C@@H:20]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[CH3:21])[N:14]=[C:15]([OH:18])[C:16]=3[N:17]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:39]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[N:40]1.CCN(C(C)C)C(C)C>C1COCC1>[N:39]1([O:18][C:15]2[C:16]3[N:17]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:9]=[CH:10][C:11]=3[N:12]=[C:13]([NH:19][C@@H:20]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:29])=[O:30])=[CH:24][CH:23]=3)[CH3:21])[N:14]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[N:40]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: C[C@@H](Nc1nc(O)c2nc(-c3ccc(F)cc3)ccc2n1)c1ccc(S(N)(=O)=O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1nc(On2nnc3ccccc32)c2nc(-c3ccc(F)cc3)ccc2n1)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-4-(1-(6-(4-fluorophenyl)-4-hydroxypyrido[3,2-d]pyrimidin-2-ylamino)ethyl)benzenesulfonamide (200 mg), BOP (479 mg) and DIEA (314 μl) in THF (10 ml) was stirred at room temperature overnight. The reaction mixture was concentrated and purified by silicon gel column chromatography (eluting with EtOAc/CH2Cl2) to provide (R)-4-(1-(4-(1H-benzo[d][1,2,3]triazol-1-yloxy)-6-(4-fluorophenyl)pyrido[3,2-d]pyrimidin-2-ylamino)ethyl)benzenesulfonamide as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:20])[C:9]([C:17]([OH:19])=[O:18])=[CH:10][N:11]2[CH2:15][CH3:16])=[CH:6][C:5]=1[F:21])(=[O:3])[CH3:2].[Br:22]([O-])(=O)=O.[K+].Br>C(O)(=O)C>[Br:22][CH2:2][C:1]([C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:20])[C:9]([C:17]([OH:19])=[O:18])=[CH:10][N:11]2[CH2:15][CH3:16])=[CH:6][C:5]=1[F:21])=[O:3]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(C(C)=O)c(F)c21
Agent: Br
Agent: [K+]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(C(=O)CBr)c(F)c21
Temperature: 50 °C
Reaction time: 24 h
Yield: 322.4 %

Procedure:
To 1.12 g (3.80 mmol) of the 7-acetyl-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 30 ml of acetic acid was added 0.18 g of potassium bromate and 1.48 ml of 48% hydrobromic acid. The mixture was stirred at 50° C. for 24 hours. The mixture was concentrated to one-half volume and 20 ml of water was added. The solids were filtered to give 1.3 g of the 7-bromoacetyl-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 213°-215° C.