Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)=[CH:4][C:3]=1[NH:23][C:24](=[O:39])[C:25]1[CH:30]=[C:29]([S:31]([F:36])([F:35])([F:34])([F:33])[F:32])[CH:28]=[C:27]([CH:37]=[O:38])[CH:26]=1.O.P([O-])(O)(O)=[O:42].[Na+].Cl([O-])=O.[Na+]>CS(C)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)=[CH:4][C:3]=1[NH:23][C:24]([C:25]1[CH:26]=[C:27]([CH:28]=[C:29]([S:31]([F:35])([F:34])([F:33])([F:36])[F:32])[CH:30]=1)[C:37]([OH:42])=[O:38])=[O:39]
Reactant: Cc1cc(C)c(-n2ccn3nc(-c4cccnc4)cc23)cc1NC(=O)c1cc(C=O)cc(S(F)(F)(F)(F)F)c1
Reactant: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)c(-n2ccn3nc(-c4cccnc4)cc23)cc1NC(=O)c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
100 mg (0.142 mmol, 80% pure) of the compound from Example 77A were dissolved in 2 ml of DMSO, and a solution of 48 mg (0.350 mmol) of sodium dihydrogenphosphate hydrate in 0.7 ml of water was added at RT. A solution of 39 mg (0.342 mmol) of sodium chlorite in 0.3 ml of water was then added dropwise. The reaction mixture was stirred at RT for 24 h and then diluted with 100 ml of water and extracted three times with in each case about 100 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and freed from the solvent on a rotary evaporator. The crude product obtained in this manner was purified by preparative HPLC (Method 32). After evaporation of the product fractions, the residue was stirred in a mixture of 2 ml of pentane, 0.5 ml of dichloromethane and 0.5 ml of diisopropyl ether for 10 min. Filtration with suction and drying of the solid under high vacuum gave 43 mg (52% of theory) of the title compound.
Reaction SMILES: CN(C)C1C=CC=CC=1.Cl[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:12].[Br:26][C:27]1[CH:36]=[C:35]([CH3:37])[C:34]([CH3:38])=[CH:33][C:28]=1[NH:29][CH:30]([CH3:32])[CH3:31]>C(Cl)Cl>[Br:26][C:27]1[CH:36]=[C:35]([CH3:37])[C:34]([CH3:38])=[CH:33][C:28]=1[N:29]([CH:30]([CH3:32])[CH3:31])[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:12]
Reactant: Cc1cc(Br)c(NC(C)C)cc1C
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cl)CC1
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Cc1cc(Br)c(N(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C(C)C)cc1C
Temperature: 25 °C

Procedure:
N,N-dimethylaniline (7.12 mL, 56.2 mmol) followed by tert-butyl 4-(chlorocarbonyl)piperidine-1-carboxylate 1-11 (42.1 mL of a 1 M solution in methylene chloride, 42.1 mmol) were added to a neat stirred mixture of 2-bromo-N-isopropyl-4,5-dimethylaniline 1-9 (6.80 g, 28.1 mmol) and N,N-dimethylamino-pyridine (172 mg, 1.40 mmol) at approximately 0° C. The resulting mixture was heated to reflux for 30 min, cooled to ambient temperature and partitioned between diethyl ether and aqueous 1 N hydrochloric acid. The organic phase was separated and washed successively with aqueous 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, brine, dried (sodium sulfate) and concentrated in vacuo to give a crude residue. Purification of the crude residue by flash chromatography over silica gel (gradient elution; 0%-40% ethyl acetate/hexanes as eluent) afforded 1-12 as a white solid.
Reaction SMILES: BrC1[C:3]([C@@H:10]([NH:20][C:21](=O)[CH2:22][N:23]2C3C(F)(F)CCC(F)(F)C=3C(C(F)F)=[N:24]2)CC2C=C(F)C=C(F)C=2)=[N:4]C(NC)=NC=1.[Br:40][C:41]1[C:42]([C@@H:51]([NH:61][C:62](=[O:68])[O:63][C:64]([CH3:67])([CH3:66])[CH3:65])[CH2:52][C:53]2[CH:58]=[C:57]([F:59])[CH:56]=[C:55]([F:60])[CH:54]=2)=[N:43][C:44](S(C)(=O)=O)=[N:45][CH:46]=1.N1(CCN)C=CN=N1>>[N:20]1([CH2:10][CH2:3][NH:4][C:44]2[N:43]=[C:42]([C@@H:51]([NH:61][C:62](=[O:68])[O:63][C:64]([CH3:67])([CH3:66])[CH3:65])[CH2:52][C:53]3[CH:58]=[C:57]([F:59])[CH:56]=[C:55]([F:60])[CH:54]=3)[C:41]([Br:40])=[CH:46][N:45]=2)[CH:21]=[CH:22][N:23]=[N:24]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(S(C)(=O)=O)ncc1Br
Reactant: CNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Agent: NCCn1ccnn1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(NCCn2ccnn2)ncc1Br

Procedure:
The title compound (23C) was prepared according to the method presented for the synthesis of compound 14A of Example 14 utilizing 23B and 2-(1H-1,2,3-triazol-1-yl)ethanamine. MS (m/z) 545.97 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])[NH:5][C:6](=[O:9])[C:7]=1[NH2:8].Cl.[C:21](N)(=N)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+]>C(O)C>[CH2:17]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:4]1[N:3]=[C:2]2[C:7](=[N:8][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:1]2)[C:6](=[O:9])[N:5]=1)[CH2:18][CH3:19]
Reactant: N=C(N)c1ccccc1
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCOc1ccccc1C1=NC(=O)C2=NC(c3ccccc3)=NC2=N1
Temperature: 165 °C

Procedure:
A mixture of 4,5-diamino-2-(2-propoxyphenyl)-pyrimidine-6-one (1.3 g), benzamidine hydrochloride (2 g) and anhydrous sodium acetate (0.9 g) was heated in an oil bath (temperature 160-170° C.) for 2 hours. The reaction mixture was digested with hot ethanol to give a solid, 0.76 g, m.p. 267-271° C. This was combined with a further sample, 0.2 g, (similarly prepared) and recrystallised from aqueous acetic acid to give the title compound, 0.74 g, m.p. 259-260° C.
Reaction SMILES: O=[C:2]1[CH2:7][C@H:6]([NH:8]C(=O)OC(C)(C)C)[C@@H:5]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])[CH2:4][CH2:3]1.Cl.[N:26]1[CH:27]=[N:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]=12.C(N(CC)CC)C.[B][B][B][B][B][B][B][B][B][B]>CO>[N:26]1[CH:27]=[N:28][N:29]2[CH2:34][CH2:33][N:32]([C@@H:2]3[CH2:7][C@H:6]([NH2:8])[C@@H:5]([C:16]4[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=4[F:24])[CH2:4][CH2:3]3)[CH2:31][C:30]=12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(=O)CC[C@@H]1c1cc(F)c(F)cc1F
Reactant: c1nc2n(n1)CCNC2
Agent: Cl
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Solvent: CCN(CC)CC
Product: N[C@H]1C[C@@H](N2CCn3ncnc3C2)CC[C@@H]1c1cc(F)c(F)cc1F
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl [(1S,2R)-5-oxo-2-(2,4,5-trifluorophenyl)cyclohexyl]carbamate (Intermediate 1, 200mg) in anhydrous methanol (8.0 mL) under nitrogen was added 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine hydrochloride (55 mg), triethylamine (0.081 mL) and decaborane (22 mg). After stirring at 50° C. for 24 h, the reaction mixture was concentrated and chromatographed by preparative TLC (silica gel, 1:4:95 ammonium hydroxide/methanol/dichloromethane). The slow moving desired compound was recovered, stirred in 4N hydrogen chloride in 1,4-dioxane for 50 min, and concentrated. The residue was purified by preparative TLC (silica, 1:9:90 ammonium hydroxide/methanol/dichloromethane) to afford the title compound. LC-MS 352.1 (M+1).
Reaction SMILES: [Br-:1].P(Br)(Br)Br.[CH2:6](O)[C:7]#[C:8][CH2:9][C:10]#[C:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(OCC)C>[Br:1][CH2:6][C:7]#[C:8][CH2:9][C:10]#[C:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: [Br-]
Reactant: CCCCCC#CCC#CCC#CCO
Agent: BrP(Br)Br
Solvent: CCOCC
Product: CCCCCC#CCC#CCC#CCBr

Procedure:
The alcohol obtained in (a) was directly converted to the corresponding bromide by adding 2 cm3 of phosphorus tribromide (0.0216 mole) to this alcohol diluted in 50 cm3 of ethyl ether. This stirred mixture under an inert atmosphere and protected from light was heated to the boiling temperature of the solvent for 2 hours and then washed at room temperature using a saturated aqueous solution of ammonium chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])[CH:6](O)[C:7](=[CH2:11])[CH2:8][CH2:9][F:10])[CH3:2].S(Br)([Br:19])=O.O>ClCCCl>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])[CH:6]=[C:7]([CH2:11][Br:19])[CH2:8][CH2:9][F:10])[CH3:2]
Reactant: C=C(CCF)C(O)C(NC=O)C(=O)OCC
Reactant: O=S(Br)Br
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)C(C=C(CBr)CCF)NC=O
Reaction time: 0.75 h

Procedure:
1.40 g (6.0 mmol) of 6-fluoro-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 14 ml of 1,2-dichloroethane, and 0.56 ml (7.2 mmol) of thionyl bromide is added dropwise at room temperature. After 45 minutes, 12 ml of water are added and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed in succession with water, 1N potassium hydrogen carbonate solution and again with water, dried over sodium sulfate, filtered and concentrated by evaporation. 4-bromomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a brownish-yellow oil.
Reaction SMILES: COC([NH:5][CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][OH:8])=O.[C:32]([O:36][C:37]([O:39]C([O-])=O)=O)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([NH:5][CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][OH:8])=[O:39])([CH3:33])([CH3:34])[CH3:35]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)NC(=O)OC
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)NC(=O)OC(C)(C)C
Yield: 93.4 %

Procedure:
2-tert-Butoxycarbonylamino-3-octadecylcarbamoyloxypropanol Ve2 is prepared by the same manner as described in (41) by using tert-butyldicarbonate instead of methyl chloroformate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[C:44]([F:48])=[CH:45][CH:46]=[CH:47][C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(I)c2c(N)ncnc21
Reactant: CC1(C)OB(c2ccc(Oc3c(F)cccc3F)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3c(F)cccc3F)cc2)c2c(N)ncnc21
Temperature: 90 °C
Reaction time: 12 h
Yield: 78.8 %

Procedure:
Into a 100 mL, 3-necked round-bottom flask purged and maintained in an inert atmosphere of nitrogen, was placed a solution of tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv) in 1,4-dioxane/water (60/15 mL), 2-[4-(2,6-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (290 mg, 0.87 mmol, 1.3 equiv), sodium carbonate (180 mg, 1.68 mmol, 2.5 equiv), and tetrakis(triphenylphosphane)palladium (40 mg, 0.03 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 90° C. in an oil bath and then concentrated under vacuum. The resulting solution was diluted with 50 mL of dichloromethane, washed with water and brine. The organics were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (20/1) to give 280 mg (79%) of tert-butyl (2R)-2-([4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[C:11]=1[CH2:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>ClCCl>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[C:11]=1[CH2:12][CH2:13][CH2:14][NH:15][C:26]([CH:23]1[CH2:25][CH2:24]1)=[O:27]
Reactant: NCCCc1c(F)ccc2c1CCO2
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCc1c(F)ccc2c1CCO2)C1CC1
Reaction time: 16 h

Procedure:
3-(2,3-Dihydro-5-fluorobenzofuran-4-yl)propylamine hydrochloride (0.27 g) in dichloromethane (5 ml) containing triethylamine (0.5 ml) was cooled in ice. Cyclopropanecarbonyl chloride (0.12 ml) was added and stirring continued at 5° for 2 h and at room temperature for 16 h. The mixture was washed with water and passed through a solid phase extraction cartridge using ethyl acetate/hexane (1:1) to give the title compound as a white solid (0.21 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[CH:3]=1.O.[NH2:24][NH2:25]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:7])[NH:24][N:25]=[C:13]2[C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:20]#[N:21])=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: NN
Reactant: COc1cc(C(=O)O)c(C(=O)c2cccc(C#N)c2)cc1Cl
Solvent: O
Solvent: CCO
Product: COc1cc2c(=O)[nH]nc(-c3cccc(C#N)c3)c2cc1Cl
Yield: 20.3 %

Procedure:
A solution of 4-chloro-2-(3-cyanobenzoyl)-5-methoxybenzoic acid (3.0 g, 9.50 mmol) in hydrazine hydrate (0.6 mL 11.4 mmol) and EtOH (40 mL) was heated at 80° C. for 2 h. The reaction mixture was diluted with water (100 mL), and the precipitate was filtered and dried to obtain 3-(7-chloro-6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzonitrile (0.6 g, 17%) (312.4 [M+H]) 1H NMR: (400 MHz, DMSO) δ: 3.96 (s, 3H), 7.64 (s, 1H), 7.79-7.75 (t, 1H), 7.87 (s, 1H), 7.96-7.94 (d, J=8, 1H), 8.04-8.02 (d, J=8, 1H), 8.09 (s, 1H), 13.03 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:26][CH2:27]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCNCC4)cc3C2=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-6-(3-(piperazin-1-yl)propoxy)-2-p-tolyl-1H-inden-1-one (30 mg, 1.2 eq, 0.063 mmol) obtained in Step 2 in CH2Cl2 at 0° C. was added triethylamine (11 mL, 1.5 eq) and methylsulfonyl chloride (4.0 mL, 1.0 eq). The mixture was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (17 mg, 74% for 2 steps).
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH:9]2[C:14](=O)[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20](O)=[O:21])[C:11]=3[O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:3]1([CH:9]2[CH:14]=[N:13][C:12]3[CH:16]=[CH:17][CH:18]=[C:19]([CH2:20][OH:21])[C:11]=3[O:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1cccc2c1OC(c1ccccc1)C(=O)N2
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc2c1OC(c1ccccc1)C=N2
Reaction time: 0.17 h
Yield: 89.2 %

Procedure:
Boron trifluoride ether complex (1.83 ml, 14.86 mmol) was added dropwise to a suspension of sodium borohydride (422 mg, 11.14 mmol) in tetrahydrofuran (30 ml) with stirring under ice cooling in 10 min. To this reaction mixture was added a solution of (±)-2-phenyl-1,4-benzoxazin-3-one-8-carboxylic acid (500 mg, 1.86 mmol) in tetrahydrofuran (6 ml) and the mixture was stirred at the same temperature for 5 min. and then at room temperature for 1.5 hrs. The reaction mixture was cooled with ice and water (20 ml) was added dropwise thereto. The mixture was neutralized with saturated sodium bicarbonate solution and then extracted with ethyl acetate. The extract was washed with water and brine in turn and dried. The solvent was distilled off under reduced pressure to give (±)-2-phenyl-1,4-benzoxazine-8-methanol (397 mg, 89%) as a pale orange oil.
Reaction SMILES: CN(C=O)C.[N+:6]([C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH2:17][C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([O:23][CH3:24])=[O:22])[CH2:14][CH2:15][O:16][C:11]=2[CH:10]=1)([O-])=O>[Zn].O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.O>[NH2:6][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH2:17][C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([O:23][CH3:24])=[O:22])[CH2:14][CH2:15][O:16][C:11]=2[CH:10]=1
Reactant: COC(=O)c1cccc(CN2CCOc3cc([N+](=O)[O-])ccc32)c1
Agent: Cl[Fe](Cl)Cl
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2CCOc3cc(N)ccc32)c1
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 87.7 %

Procedure:
DMF (5 mL), water (5 mL), zinc (0.7 g, 10.7 mmol) and iron trichloride hexahydrate (0.12 g, 0.4 mmol) were added to methyl 3-[(7-nitro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methyl]benzoate obtained in Example (100a) (0.35 g, 1.07 mmol), and the mixture was stirred at 100° C. for 50 minutes. The insoluble matter was filtered off and ethyl acetate was added to the mother liquor, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave 0.28 g of the crude title compound as a brown oily substance (88%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:38]([O-])=[O:39].[NH4+]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:20][CH2:21][N:22]([CH:38]=[O:39])[CH2:23][CH2:24]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C[O-]
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCNCC3)c2=O)cc1OC
Agent: [NH4+]
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCN(C=O)CC3)c2=O)cc1OC
Yield: 97.9 %

Procedure:
A mixture of 0.6 g of 6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-1-(piperidin-4-yl)quinazoline-2,4(1H,3H)-dione obtained in stage 1.6 and 0.113 g of ammonium formate in 5 ml of ACN is irradiated under a microwave field at 140° C. for 1 h 00. The mixture is filtered and the filtrate is evaporated under reduced pressure to give 0.62 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:19](=[O:20])[O:21][CH2:22][CH3:23])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NCc1ccc(OC)cc1
Temperature: 25 °C
Yield: 43.6 %

Procedure:
A stirred solution of 6.0 mL (0.046 mole) of 4-methoxyphenylmethyl-amine and 6.5 mL (0.047 mole) of triethylamine in 200 mL of tetrahydrofuran was cooled to about 5° C., and a solution of 4.4 mL (0.046 mole) of ethyl chloroformate in 10 mL of tetrahydrofuran was added. Upon completion of the addition the reaction mixture was allowed to warm to ambient temperature, then was poured into a mixture of 200 mL of ice and 200 mL of an aqueous solution saturated with ammonium chloride. This mixture was extracted with 300 mL of diethyl ether, and the extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 4.2 grams (43.8% yield) of ethyl (4-methoxyphenylmethyl)-carbamate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:14][CH2:15][CH2:16][Cl:17]>C(#N)C>[Cl:17][CH2:16][CH2:15][CH2:14][N:2]([CH3:1])[CH:3]1[CH2:6][CH2:5][CH2:4]1
Reactant: CNC1CCC1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCCl)C1CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.3 %

Procedure:
To a solution of N-methylcyclobutanamine (1 g, 3.89 mmol) and potassium carbonate (1.18 g, 8.56 mmol) in acetonitrile (20 ml) at 0° C. was added 1-bromo-3-chloropropane (383 μl, 3.89 mmol). Reaction was warmed to room temperature and stirred for 24 hours. Solid removed by filtration and filtrate concentrated in vacuo to give the title compound (241 mg, 38%) as an oil. No purification was performed. LRMS APCI+ m/z 162 [MH]+.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1([CH3:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([N:20]2[CH2:21][CH2:22][CH2:23][C:18]([CH3:24])([CH3:17])[CH2:19]2)=[O:9])[CH:3]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: CC1(C)CCCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)CCCN(C(=O)c2csc(Br)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
5-Bromothiophene-3-carboxylic acid (0.5 g, 2.4 mmol) was dissolved in acetonitrile (10 mL) and triethylamine (7.1 mmol). 3,3-Dimethylpiperidine (2.4 mmol) and HATU (2.4 mmol) were added and the reaction stirred at room temperature overnight. The solvent was evaporated and the residue dissolved in DCM and washed with water. After drying with anhydrous magnesium sulphate, the solution was filtered and evaporated and the residue purified by flash chromatography on silica, eluting with 0-40% ethyl acetate in cyclohexane. The fractions containing the desired product were combined and evaporated to give the title compound as a white crystalline solid (0.475 g). 1H NMR δ (ppm)(CHCl3-d): 7.4 (s, 1H), 7.1 (s, 1H), 3.6-3.1 (m, 4H), 1.7 (m, 2H), 1.4 (m, 2H), 0.9 (s, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)[CH3:10].[CH3:20][O:21][C:22](=[O:49])[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([O:32][C:33]2[C:34]3[C:41](Br)=[C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[O:39][C:35]=3[N:36]=[CH:37][N:38]=2)[CH2:27]1>CS(C)=O.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>[CH3:20][O:21][C:22](=[O:49])[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([O:32][C:33]2[C:34]3[C:41]([C:14]4[CH:15]=[CH:16][C:11]([CH2:9][CH3:10])=[CH:12][CH:13]=4)=[C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[O:39][C:35]=3[N:36]=[CH:37][N:38]=2)[CH2:27]1
Reactant: COC(=O)CCCN1CCC[C@H](Oc2ncnc3oc(-c4ccccc4)c(Br)c23)C1
Reactant: CCc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@H]4CCCN(CCCC(=O)OC)C4)c23)cc1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
Add 5.2 mg (0.007 mmol) of bis(triphenylphosphine)palladium(II) chloride,. 30.6 mg (0.221 mmol) of potassium carbonate, 0.04 ml of methanol and 31 mg (0.207 mmol) of 4-ethylbenzeneboronic acid successively under argon to a solution of 70 mg (0.148 mmol) of (+)-4-{(3S)-3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]piperidin-1-yl}butanoic acid methyl ester in 0.4 ml of DMSO. Stir the mixture at 80° C. for a total of 3.5 h. After cooling, purify the reaction mixture directly by preparative RP-HPLC (eluent: acetonitrile/water gradient). 37.3 mg (50.6% of theory) of the target compound are isolated.