Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:41])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])=[CH:24][CH:23]=1>>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:29]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:2]3[CH:11]=[CH:10][N:9]=[C:8]4[C:3]=3[C:4]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:5]=3[C:6](=[O:12])[NH:7]4)=[CH:27][CH:26]=2)=[O:41])=[C:31]([C:37]([F:38])([F:39])[F:40])[CH:32]=1
Reactant: Nc1ccc(NC(=O)c2ccc(F)cc2C(F)(F)F)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2cc(C(F)(F)F)ccc12
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4ccc(C(F)(F)F)cc4c23)cc1)c1ccc(F)cc1C(F)(F)F

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 378, method 2 using 1-chloro-9-trifluoromethyl-5H-benzo[c][1,8]naphthyridin-6-one and N-(4-amino-phenyl)-4-fluoro-2-trifluoromethyl-benzamide to provide 404. LC-MS (M+H=561, obsd.=561). 1H NMR (400 MHz, DMSO-d6): δ, 6.96 (d, 1H), 7.18 (d, 2H), 7.54 (m, 2H), 7.76 (m, 2H), 7.78 (d, 1H), 7.97 (d, 1H), 8.10 (d, 1H), 8.27 (s, 1H), 8.99 (s, 1H), 10.25 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([Si](CC)(CC)CC)=[C:5]2[CH2:19][CH2:20][NH:21][C:22]([C:24]1[CH:28]=[C:27]([CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[F:37])[O:26][N:25]=1)=[O:23]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:19][CH2:20][NH:21][C:22]([C:24]1[CH:28]=[C:27]([CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[F:37])[O:26][N:25]=1)=[O:23]
Reactant: CC[Si](CC)(CC)c1[nH]c2c(F)cc(Cl)cc2c1CCNC(=O)c1cc(Cc2cc(F)ccc2F)on1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCc1c[nH]c2c(F)cc(Cl)cc12)c1cc(Cc2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.5 %

Procedure:
N-(2-(5-chloro-7-fluoro-2-(triethylsilyl)-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide (0.050 g; 0.092 mmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at room temperature for 3 hours. The solution was concentrated under reduced pressure and the crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.005 g (12%) of N-(2-(5-chloro-7-fluoro-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][NH:39][CH2:40][CH2:41][OH:42]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:39]([CH2:40][CH2:41][OH:42])[CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CNCCO
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CN(CCO)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 2-methylaminoethanol according to conditions described in general procedure C. Mp: 100-102° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.77-3.52 (m, 4 H), 3.26 (s, 4 H), 3.76 (m, 4 H), 4.62 (m, 1 H), 6.19-6.22 (m, 1 H), 7.02-7.05 (m, 1 H), 7.26 (d, J=8.4 Hz, 1 H), 7.41 (d, J=8.0 Hz, 1 H), 7.50 (s, 1 H), 7.56-7.63 (m, 3 H), 7.85 (d, J=7.6 Hz, 1 H), 8.00 (d, J=7.6 Hz, 1 H), 8.25 (d, J=5.4 Hz, 1 H), 10.47 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](OCC)=[O:14])[CH:10]=[N:9]2)=[C:5]([CH3:18])[O:4][N:3]=1.[NH2:19][NH2:20]>CCO>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([NH:19][NH2:20])=[O:14])[CH:10]=[N:9]2)=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cnn(Cc2c(C)noc2C)c1
Solvent: CCO
Product: Cc1noc(C)c1Cn1cc(C(=O)NN)cn1
Yield: 97.4 %

Procedure:
Ethyl 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carboxylate (example 10-1c) (6 g, 24 mmol) and hydrazine (7.5 g, 240 mmol) were stirred in EtOH (100 mL) at reflux for 12 hours. The solution was concentrated on the rotovap and the solid product was triturated with ethyl acetate/hexanes (1/9) and dried under high vacuum to afford 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carbohydrazide (5.5 g, 97%) as a pure white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.11 (s, 3H), 2.39 (s, 3H), 5.15 (s, 2H), 7.81 (s, 1H), 8.17 (s, 1H), 9.31 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](I)=[C:4]([CH3:17])[C:5]([C:15]#[N:16])=[C:6]2[C:10]=1[O:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:7]2.[C:19]1(B2OCCCO2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>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.CN(C)C=O>[Br:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([CH3:17])[C:5]([C:15]#[N:16])=[C:6]2[C:10]=1[O:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:7]2
Reactant: Cc1c(I)c(Br)c2oc(C(C)(C)C)nc2c1C#N
Reactant: c1ccc(B2OCCCO2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)c(Br)c2oc(C(C)(C)C)nc2c1C#N
Temperature: 100 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.26 mmol) was added to an N,N-dimethylformamide (60 ml) suspension of 7-bromo-2-tert-butyl-6-iodo-5-methyl-1,3-benzoxazole-4-carbonitrile (I-8) (545 mg, 1.30 mmol), 2-phenyl-1,3,2-dioxaborinane (205 μl, 1.37 mmol), anhydrous potassium phosphate (552 mg, 2.60 mmol), followed by stirring at 100° C. for 1 hour. After cooling, 1 N hydrochloric acid (100 ml) was added, the product was extracted with ethyl acetate (100 ml×2), the organic layer was washed with saturated brine (50 ml×2), then dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:1→6:1) to obtain the entitled compound (210 mg, 44%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\C1C=C(F)C=CC=1S(NC1C(C(OC)=O)=C2C(C3C=COC=3CO2)=CC=1)(=O)=O)[CH3:2].Br[C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[S:45]([N:48]([C:53]1[C:62]([C:63]([O:65][CH3:66])=[O:64])=[C:61]2[C:56]([C:57]3[CH2:69][CH2:68][O:67][C:58]=3[CH:59]=[N:60]2)=[CH:55][CH:54]=1)[C:49]([O:51][CH3:52])=[O:50])(=[O:47])=[O:46].C(N(CC)C/C=C\[Sn](CCCC)(CCCC)CCCC)C>>[CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[S:45]([N:48]([C:53]1[C:62]([C:63]([O:65][CH3:66])=[O:64])=[C:61]2[C:56]([C:57]3[CH2:69][CH2:68][O:67][C:58]=3[CH:59]=[N:60]2)=[CH:55][CH:54]=1)[C:49]([O:51][CH3:52])=[O:50])(=[O:47])=[O:46])[CH3:2]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2Br)ccc2c3c(cnc12)OCC3
Agent: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)N(C(=O)OC)c1ccc2c3c(cnc2c1C(=O)OC)OCC3
Temperature: 60 °C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 9, starting from methyl 7-[N-(2-bromo-4-fluorobenzenesulfonyl)-N-(methoxycarbonyl)amino]-1,2-dihydro-furo[2,3-c]quinoline-6-carboxylate (Intermediate 21) and N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)amine (Intermediate 11) and heating at 60° C. for 1 hour.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C@@:6]12[CH2:13][CH2:12][C@@H:11]1[CH2:10][CH2:9][C:8](Br)([Br:14])[C:7]2=[O:16])[CH3:2].C(=O)([O-])[O-].[Li+].[Li+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C@@:6]12[CH2:13][CH2:12][C@@H:11]1[CH2:10][CH:9]=[C:8]([Br:14])[C:7]2=[O:16])[CH3:2]
Reactant: CCOC(=O)C[C@@]12CC[C@@H]1CCC(Br)(Br)C2=O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@@]12CC[C@@H]1CC=C(Br)C2=O
Temperature: 100 °C
Yield: 54.9 %

Procedure:
cis-3,3-Dibromo-2-oxobicyclo[4.2.0]-octane-1-acetic acid ethyl ester (14.16 g) lithium bromide (4.88 g, 56.21 mmol), and lithium carbonate (2.98 g, 14.4 mmol) were dissolved in 47.3 mL of DMF under nitrogen and heated to 100° C. for 5 minutes. The reaction mixture was then poured into 500 mL of water and extracted with 4×100 mL of toluene. The organic phase was washed with 4×100 mL of water, dried over MgSO4, and concentrated in vacuo affording 8.86 g (80%) of product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O.[C:12]1([S:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:7][C:15]2[CH:16]=[CH:17][C:12]([S:18][CH3:19])=[CH:13][CH:14]=2)[CH:10]=1
Reactant: CSc1ccccc1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Product: CSc1ccc(Cc2cc(Br)ccc2Cl)cc1

Procedure:
Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-chlorobenzoic acid and thioanisole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:26][CH3:27])[C:5]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[C:7]2[CH3:14].C(NC(C)C)(C)C.I[CH:36]([CH3:51])[CH2:37][CH2:38][CH2:39][N:40]1[C:44](=[O:45])[C:43]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]2[C:41]1=[O:50]>CC#N.O>[CH3:13][O:12][C:9]1[CH:8]=[C:7]([CH3:14])[C:6]2[C:11](=[C:2]([NH:1][CH:36]([CH3:51])[CH2:37][CH2:38][CH2:39][N:40]3[C:44](=[O:45])[C:43]4=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]4[C:41]3=[O:50])[CH:3]=[C:4]([O:26][CH3:27])[C:5]=2[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)[N:10]=1
Reactant: CC(I)CCCN1C(=O)c2ccccc2C1=O
Reactant: COc1cc(C)c2c(Oc3cccc(C(F)(F)F)c3)c(OC)cc(N)c2n1
Solvent: CC(C)NC(C)C
Solvent: CC#N
Solvent: O
Product: COc1cc(C)c2c(Oc3cccc(C(F)(F)F)c3)c(OC)cc(NC(C)CCCN3C(=O)c4ccccc4C3=O)c2n1
Reaction time: 24 h

Procedure:
A mixture of 8-amino-2,6-dimethoxy-4-methyl-5-(3-trifluoromethylphenoxy)quinoline (8.0 g, 21.2 mmol), diisopropylamine (2.14 g, 21.2 mmol) and 4-iodo-1-phthalimidopentane (IPP) (7.26 g, 21.2 mmol) in CH3CN (40 mL) was refluxed for 24 hours after which time additional diisopropylamine (2.14 g, 21.2 mmol) and IPP (7.26 g, 21.2 mmol) were added. After refluxing a further 24 hours, more diisopropylamine (1.07 g, 10.6 mmol) and IPP (3.63 g, 10.6 mmol) were added and refluxing was continued a further 24 hours. The cooled mixture was diluted with H2O (20 mL) and stirred in an ice bath until crystallization was complete. Filtration and recrystallization from IPA gave 8.4 g (67%) of 1st crop title compound, mp 120°-124° C. Further recrystallization raised the mp to 121°-124° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:29]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:30]=[CH:31][C:26]([S:23]([N:22]2[CH2:21][CH2:20][S:19][CH:18]2[C:16]([NH:15][CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][CH2:6][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:17])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Reactant: C1CCNC1
Product: O=C(NC(CCN1CCCC1)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method A as outlined in Example 16, starting from 3-({[3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and pyrrolidine, the title compound was obtained in 99.2% purity by HPLC.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH2:19][CH:20]=[CH2:21])[C:11]([OH:18])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:22].[O-:23][C:24]#[N:25].[K+]>O>[CH2:19]([C:10]1[C:11]([OH:18])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:13]=[C:14]2[C:9]=1[CH2:8][CH2:7][C:6](=[O:22])[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][C:24]([NH2:25])=[O:23])[CH:20]=[CH2:21]
Reactant: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCN
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Product: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCCNC(N)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
1.68 Grams of 1-(3-aminopropyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone was dissolved in 100 ml of water, then 10 ml of an aqueous solution containing 1 g of potassium cyanate was added thereto under ice-cooling condition, and stirred at room temperature for 12 hours. The crystals thus precipitated were collected by filtration and washed with water, there was obtained 0.5 g (29%) of 5,7-diallyl-3,4-dihydro-6-hydroxy-1-(3-ureidopropyl)-2(1H)-quinolinone.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH2:12][NH2:13].C(N(CC)CC)C>C(O)C.O>[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH2:12][NH:13][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccn1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: COc1ccc(CNc2ncccn2)c(OC)c1
Temperature: 120 °C
Yield: 72.7 %

Procedure:
A mixture of 2-chloropyrimidine (1.37 g, 12 mmol), 2,4-dimethoxybenzylamine (2.61 g, 15.6 mmol) and triethylamine (2.51 mL, 18 mmol) in ethanol (8 mL) was heated in a Biotage Initiator™ microwave at 120° C. for 15 minutes. The reaction mixture was diluted with water and extracted with dichloromethane (×3). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20-50% ethyl acetate in heptane gradient elution) to afford the title compound as a white solid (2.14 g, 72%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[N:8]2[N:9]=[C:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:19][CH2:18]3)[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:37]([CH3:44])([CH3:43])[C:38]([O:40]CC)=[O:39].[OH-].[Na+]>C(O)C>[Cl:3][C:4]1[N:8]2[N:9]=[C:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][CH:20]([O:23][CH:24]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:21][CH2:22]3)[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:37]([CH3:44])([CH3:43])[C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)C(C)(C)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1Cl
Yield: 84 %

Procedure:
653 mg of ethyl 2-[3-chloro-6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate dihydrochloride was dissolved in 6 ml of ethanol; 1.97 ml of a 2 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 2.5 hours. After cooling, the mixture was concentrated under reduced pressure; the residue was diluted with water and washed with ethyl acetate; the water layer was ajusted to pH 4.5 by the addition of 1 N hydrochloric acid. Acetone was added; the crystal precipitated was collected by filtration, washed with water-acetone (5:1) and dried to yield 465 mg of the title compound.
Reaction SMILES: [CH2:1]([P:8]([O:13][CH2:14][CH3:15])(=[O:12])[O:9][CH2:10][CH3:11])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7].CI.[CH2:18](P(OCC)(=O)OCC)C=CC.C(Br)C1C=CC=CC=1>>[CH3:18][CH:1]([P:8]([O:9][CH2:10][CH3:11])(=[O:12])[O:13][CH2:14][CH3:15])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC=CCP(=O)(OCC)OCC
Reactant: CC=CCP(=O)(OCC)OCC
Agent: BrCc1ccccc1
Solvent: CI
Product: CCCCC=CC(C)P(=O)(OCC)OCC
Yield: 89.9 %

Procedure:
The same procedure as in Example A-1 was repeated except that 2,34 g of diethyl 2-heptenephosphonate and 1.42 g of methyl iodide were used instead of 1.92 g of the diethyl 2-butenephosphonate and 1.7 g of the benzyl bromide respectively. Vacuum distillation of the reaction mixture afforded 2.23 g of diethyl 1-methyl-2-heptene-phosphonate having a boiling point of 128° C. (3 mmHg) in a yield of 90%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[OH:26][C@H:25]([CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H]1CO1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H](O)CN1CCCC1
Temperature: 75 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
A mixture of (2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (300 mg, 0.83 mmol), and pyrrolidine (176 mg, 2.48 mmol) in DMF (5 ml) was stirred at 75° C. for 3 hours under an atmosphere of nitrogen and allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified on silica gel, gradient elution with dichloromethane, dichloromethane/methanol (95/5), dichloromethane/methanolic ammonia (7M) (98/2 to 90/10), to give (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (326 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH:18]([C:20]4[O:24][N:23]=[C:22]([CH3:25])[N:21]=4)[CH2:19][CH:12]2[CH2:13][C:14](=[O:26])[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:27](OCC)=[O:28].[O-]CC.[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:12]3[CH2:19][CH:18]([C:20]4[O:24][N:23]=[C:22]([CH3:25])[N:21]=4)[CH2:17][CH:16]2[C:15](=[CH:27][OH:28])[C:14](=[O:26])[CH2:13]3)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC=O
Reactant: Cc1noc(C2CC3CC(=O)CC(C2)N3S(=O)(=O)c2ccc(Cl)cc2)n1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1noc(C2CC3CC(=O)C(=CO)C(C2)N3S(=O)(=O)c2ccc(Cl)cc2)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
9-[(4-Chlorophenyl)sulfonyl]-7-(3-methyl-1,2,4-oxadiazol-5-yl)-9-azabicyclo[3.3.1]nonan-3-one (52) (0.357 g, 0.902 mmol) was dissolved in THF/EtOH (2 mL, 1/1, v/v). Ethyl formate (0.725 mL, 9.02 mmol) was added followed by sodium ethoxide (1.01 mL of 21% solution in EtOH). The resulting mixture was stirred at 50° C. for 1 hour after which the solution was cooled back to room temperature and quenched by the addition of saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc and the combined organic phases were dried (Na2SO4), filtered and concentrated under vacuum to give 9-[(4-chlorophenyl)sulfonyl]-2-(hydroxymethylidene)-7-(3-methyl-1,2,4-oxadiazol-5-yl)-9-azabicyclo[3.3.1]nonan-3-one (53). MS (ESI) 424.0 (M+H).
Reaction SMILES: [Si:1]([N:8]1[C:14](=[O:15])[C@@H:13]2[C@H:9]1[C@@H:10]([OH:26])[CH2:11][N:12]2[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C([O-])=O)CCCCC>>[CH2:19]([O:18][C:16]([N:12]1[CH2:11][C:10](=[O:26])[C@@H:9]2[C@H:13]1[C:14](=[O:15])[N:8]2[Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H]2[C@H]1[C@@H](O)CN2C(=O)OCc1ccccc1
Agent: CCCCCC(C)C(=O)[O-]
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H]2[C@H]1C(=O)CN2C(=O)OCc1ccccc1

Procedure:
(1S,5S)-6-(t-Butyl-dimethyl-silanyl)-4,7-dioxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylic acid benzyl ester was prepared from benzyl (1S,4S,5S)-6-(t-butyldimethylsilanyl)-4-hydroxy-7-oxo-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate in the same manner as described for benzyl (1S,5S)-6-(3,4-dimethoxybenzyl)-4,7-dioxo-2,6-diazabicyclo[3.2.0.]heptane-2-carboxylate (Example 7).
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=2)[CH:9]=[CH:8][C:7]=1[N+:20]([O-])=O.N#N>[Pt].C(OCC)(=O)C>[F:1][C:2]1[CH:26]=[C:25]([O:27][C:28]([F:30])([F:29])[F:31])[CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C:6]1[C:7]([NH2:20])=[CH:8][CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=2)[CH:11]=1
Reactant: Cn1ccc(COc2ccc([N+](=O)[O-])c(NCc3ccc(OC(F)(F)F)cc3F)c2)n1
Agent: [Pt]
Agent: N#N
Solvent: CCOC(C)=O
Product: Cn1ccc(COc2ccc(N)c(NCc3ccc(OC(F)(F)F)cc3F)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.9 %

Procedure:
In a high pressure reactor a solution of N-(2-fluoro-4-(trifluoromethoxy)benzyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)-2-nitroaniline (80.0 g, 0.18 mol), 5% Pt/C (50% H2O, Johnson Matthey B102022-5) (7.1 g, 0.91 mmol) and ethyl acetate (800 mL) was filled twice with N2 (60 psi) then twice with H2 (60 psi). The flask was then filled with H2 (60 psi) and let stir at RT 15 h. The reaction mixture was filtered (zapcap brand filter), the solid was rinsed with EtOAc (2×200 mL). The filtrate was concentrated to dryness to afford the title compound as a brown oil (74.5 g, 99.5%). This material was used without further purification. MS (ESI): mass calcd. for C19H18F4N4O2, 410.1; m/z found, 411.1 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 7.42-7.35 (m, 1H), 7.33-7.29 (d, J=2.2, 1H), 7.01-6.94 (d, J=9.2, 1H), 6.71-6.66 (d, J=8.3, 1H), 6.37-6.31 (dd, J=8.3, 2.7, 1H), 6.31-6.26 (m, 1H), 4.98-4.94 (s, 1H), 4.41-4.33 (s, 1H), 3.93-3.85 (s, 2H), 3.35-2.72 (s, 1H).
Reaction SMILES: C([N:8]1[C@H:13]([CH3:14])[CH2:12][N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([CH3:23])[CH:16]=2)[C@@H:10]([CH3:24])[CH2:9]1)C1C=CC=CC=1.C(Cl)(=O)OC(Cl)C>ClC(Cl)C>[CH3:24][C@H:10]1[CH2:9][NH:8][C@H:13]([CH3:14])[CH2:12][N:11]1[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([CH3:23])[CH:16]=1
Reactant: Cc1cc(N2C[C@@H](C)N(Cc3ccccc3)C[C@@H]2C)ccc1C#N
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: Cc1cc(N2C[C@@H](C)NC[C@@H]2C)ccc1C#N
Yield: 85.4 %

Procedure:
Into 50 ml of dichloroethane was dissolved 1.81 g of 4-[(2S,5R)-4-benzyl-2,5-dimethylpiperazin-1-yl]-2-methylbenzonitrile, and then 1.62 g of 1-chloroethyl chlorocarbonate was added thereto, followed by heating under refluxing overnight. After the reaction solution was concentrated, 50 ml of methanol was added thereto, followed by heating under refluxing overnight. After the reaction solution was concentrated, water was added thereto, followed by washing with ether. The aqueous phase was made basic with a 1M sodium hydroxide aqueous solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then solvent was removed by evaporation to obtain 1.11 g of the title compound.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1>ClCCl>[Br:1][C:8]1[CH:9]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=1[OH:10]
Reactant: BrBr
Reactant: Oc1ccc(F)cc1
Solvent: ClCCl
Product: Oc1ccc(F)cc1Br
Reaction time: 24 h

Procedure:
At -20° C., 15.3 ml of bromine is dripped into 33.6 g of 4-fluorophenol in 300 ml of dichloromethane. After the solution has stood for 24 hours it is colorless. Distillation gives 46 g of 2-bromo-4-fluorophenol of boiling point 70° C./13.3 mbars.