Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:7]1[CH2:11][C:10](=[CH2:12])[CH2:9][C@H:8]1[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=O)C=C.O.CCCC[SnH](CCCC)CCCC>C(Cl)Cl.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>[Si:15]([O:14][CH2:13][C@@H:8]1[CH2:9][C:10](=[CH2:12])[CH2:11][NH:7]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17]
Reactant: C=CCOC(=O)N1CC(=C)C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: ClCCl
Product: C=C1CN[C@H](CO[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A catalytic amount of PdCl2(PPh3)2 (92 mg, 0.131 mmol) was added to a solution of the allyl carbamate 57 (1.0 g, 3.22 mmol) and H2O (0.34 mL, 18.9 mmol) in CH2Cl2 (30 mL). After 5 minutes stirring at room temperature, Bu3SnH (0.96 mL, 1.04 g, 3.57 mmol) was added rapidly in one portion. A slightly exothermic reaction with vigorous gas evolution immediately ensued. The mixture was stirred for 16 hours at room temperature under nitrogen at which point TLC (50% EtOAc/Petroleum Ether) revealed the formation of amine. After diluting with CH2Cl2 (30 mL), the organic solution was dried (MgSO4), filtered and evaporated in vacuo to give an orange oil which was purified by flash chromatography (50-100% EtOAc/Petroleum Ether) to afford the amine 58 as a slightly orange oil (0.56 g, 77%): [α]21D=−3.9° (c=5.0, CHCl3); 1H NMR (270 MHz, CDCl3) δ 4.93 (t, 1H, J=2.02 Hz, NCH2C═CH2), 4.90 (t, 1H, J=2.02 Hz, NCH2C═CH2), 3.68-3.46 (m, 4H, NCHCH2OTBDMS and NCH2C═CH2), 3.30-3.21 (m, 1H, NCHCH2OTBDMS), 2.53-2.41 (m, 2H, NCH2C═CH2CH2 and NH), 2.26-2.17 (m, 1H, NCH2C═CH2CH2), 0.90 (s, 9H, SiC(CH3)3), 0.06 (s, 6H, Si(CH3)3); 13C NMR (67.8 MHz, CDCl3) δ 150.0 (NCH2C═CH2), 104.7 (NCH2C═CH2), 64.7 (NCHCH2OTBDMS), 60.5 (NCHCH2OTBDMS), 51.3 (NCH2C═CH2), 34.9 (NCH2C═CH2CH2), 25.9 (SiC(CH3)3), 18.3 (SiC(CH3)3), −5.4 (Si(CH3)2); MS (EI), m/z (relative intensity) 227 (M+., 8), 212 (6), 170 (M-tBu, 36), 96 (8), 82 (M-CH2OTBDMS, 100), 75 (11); IR (Neat) 3550-3100 (br, NH), 3074 (C═CH2), 2929, 2857, 1664 (C═C), 1472, 1424, 1391, 1380, 1361, 1255, 1190, 1101, 1006, 939, 880, 838, 777, 723, 668 cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH2:10][CH2:11][OH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1
Reactant: OCCBr
Reactant: Nc1cccc(Br)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OCCNc1cccc(Br)c1
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of 3-bromo-aniline (0.037 mol), 2-bromo-ethanol (0.074 mol) and triethylamine (0.0555 mol) in toluene (35 ml) was stirred under reflux for 12 hours. The reaction was cooled down to room temperature and the precipitate was filtered off. The solvent of the filtrate was evaporated until dryness. The residue (22 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 98/2/0.1; 20-45 μm). The pure fractions were collected and the solvent was evaporated, yielding 4.8 g of 2-(3-bromo-phenylamino)-ethanol (60%).
Reaction SMILES: C[O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=4)[CH2:19][CH2:18]3)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.Br>O>[OH:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([OH:2])=[CH:33][CH:32]=4)[CH2:13][CH2:12]3)[CH2:18][CH2:19]2)=[CH:29][CH:28]=1
Reactant: COc1ccc(CN2CCN(CCCN3CCN(Cc4ccc(OC)cc4)CC3)CC2)cc1
Agent: Br
Solvent: O
Product: Oc1ccc(CN2CCN(CCCN3CCN(Cc4ccc(O)cc4)CC3)CC2)cc1
Yield: 30.8 %

Procedure:
A mixture of 4.5 g of 1,3-bis[4-(4-methoxybenzyl)-1-piperazinyl]propane from Example 19 and 125 ml of 49% hydrobromic acid was refluxed for 2 hours and was then cooled and diluted with 125 ml of water. After filtration the aqueous solution was neutralized with 2N sodium hydroxide to adjust the pH to 8. The resulting mixture was extracted three times each with 150 ml of ethanol. The alcohol was then removed by rotary evaporation and the residue was chromatographed on silica with the eluant being methylene chloride containing 1% ammonium hydroxide and 10% methanol to obtain 1.3 g (31% of theory) of 1,3-bis[4-(4-hydroxybenzyl)-1-piperazinyl]propane as a white crystalline product, melting at 197°-201° C.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[C:14]3[CH:13]=[CH:12][C:11]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:10][C:9]=3[NH:8][N:7]=2)=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35].O>CN(C)C=O>[CH:1]1([C:4]([C:6]2[C:14]3[CH:13]=[CH:12][C:11]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:10][C:9]=3[N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:7]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C(c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(C(=O)C2CC2)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Temperature: 20 °C
Yield: 70.9 %

Procedure:
A solution of 2.55 g of cyclopropyl(6,6-diphenyl-6,7-dihydro-1H-indazol-3-yl)methanone in 40 cm3 of dimethylformamide is added dropwise at a temperature in the region of 5° C. to a suspension, cooled to this same temperature, of 0.39 g of sodium hydride (at 60% in oil) in 20 cm3 of dimethylformamide. After stirring the mixture at this same temperature for about one and a half hours, a solution of 1.87 g of (2-chloromethoxyethyl)trimethylsilane in 20 cm3 of dimethylformamide is added dropwise without exceeding a temperature of 10° C. After warming to a temperature in the region of 20° C., the mixture is stirred for 2 hours at this same temperature. 20 cm3 of water are then added and the mixture is concentrated under reduced pressure (13 kPa). The residue is taken up in 80 cm3 of water and extracted three times with 60 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. After flash chromatography on a column of silica [eluent: dichloromethane/methanol (99/1 by volume)], 2.5 g of cyclopropyl(6,6-diphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazol-3-yl)methanone are thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH:14]=O>>[CH3:9][O:10][C:11]1[CH:12]=[C:13](/[CH:14]=[C:6](/[C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)\[C:7]#[N:8])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: N#CCc1ccsc1
Reactant: COc1ccc(C=O)cc1OC
Product: COc1ccc(/C=C(\C#N)c2ccsc2)cc1OC
Yield: 65.3 %

Procedure:
3-Thiopheneacetonitrile (246 mg) was condensed with 3,4-dimethoxybenzaldehyde (332 mg) through Method B (production step 2), to thereby yield the target product (yield: 354 mg, 65%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[C:7]1=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCOCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[C:7]2=[O:18])[CH2:29][CH2:30]1
Reactant: O=C1CCc2ccccc2C(=O)N1CCCCBr
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: C1COCCO1
Product: O=C1CCc2ccccc2C(=O)N1CCCCN1CCN(c2ccccn2)CC1
Yield: 91 %

Procedure:
To a solution of 101 mg of the compound of Example 16 dissolved in 10 ml of dioxane was added 0.152 ml (3 equivalents) of 1-(2-pyridyl)piperazine, followed by heating under reflux for 8 hours. The reaction treatment and purification were conducted in the same manner as in Example 17 to obtain 116 mg of the desired compound (yield 91%). The maleate was obtained by converting the product to maleate in a conventional manner, followed by recrystallization from methylene chloride-ether.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([CH:30]([OH:32])[CH3:31])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([CH:30]([OH:32])[CH3:31])=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Cc1nc(Cl)ccc1C(C)O
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1C(C)O

Procedure:
The title compound was prepared in the same manner described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 1-(6-chloro-2-methylpyridin 3-yl)ethanol (82 mg, 0.48 mmol) as starting materials.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])(=[O:13])=[O:12])[CH:3]=1.[CH2:24]([Sn](CCCC)(CCCC)C=C)[CH2:25]CC>C(#N)C>[CH3:23][O:22][C:16]1[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=1[NH:14][S:11]([C:4]1[CH:3]=[C:2]([CH:24]=[CH2:25])[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1)(=[O:13])=[O:12]
Reactant: COc1ccc(C)cc1NS(=O)(=O)c1cc(I)c2occc2c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: C=Cc1cc(S(=O)(=O)Nc2cc(C)ccc2OC)cc2ccoc12
Temperature: 180 °C
Yield: 582.4 %

Procedure:
Five batches each consisting of a mixture of N-(2-methoxy-5-methylphenyl)-7-iodo-1-benzofuran-5-sulfonamide (443 mg, 1.0 mmol; Intermediate 57), tributyl(vinyl)tin (350 mg, 1.1 mmol) and bis(triphenylphosphine)palladium diacetate (15 mg, 0.02 mmol) in acetonitrile (3 mL) was heated in a Smith Creator microwave oven to 180° C. for 5 min. The combined reaction mixtures were filtered and concentrated to give 2.0 g of crystalline crude material that was put through a SiO2 column using EtOAc/hexane (gradient 5:95→25:75) as eluent giving 1.3 g (75%) of off-white crystalline product. 1H NMR (400 MHz, CDCl3) δ 2.26 (s, 3H), 3.53 (s, 3H), 5.56 (dd, 1H), 6.16 (dd, 1H), 6.57 (d, 1H), 6.79-6.98 (m, 4H), 7.38 (d, 1H), 7.71-7.74 (m, 2H), 7.94 (d, 1H); MS (ESI+) for C18H17NO4S m/z 344 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:4]=1[NH2:5].C[O:13][C:14]1[C:22]([O:23]C)=[CH:21][CH:20]=[CH:19][C:15]=1C(O)=O>>[OH:10][C:8]1[CH:7]=[CH:6][C:4]2[N:5]=[C:1]([C:21]3[CH:20]=[CH:19][CH:15]=[C:14]([OH:13])[C:22]=3[OH:23])[O:2][C:3]=2[CH:9]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: COc1cccc(C(=O)O)c1OC
Product: Oc1ccc2nc(-c3cccc(O)c3O)oc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,4-dimethoxyaniline, and 2,3-dimethoxybenzoic acid and was obtained as a tan solid, m.p. 256–258° C.; MS m/e 244 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]2[N:12]([CH2:15][C:16]3[C:17]([F:27])=[C:18]4[C:23](=[CH:24][C:25]=3[F:26])[N:22]=[CH:21][CH:20]=[CH:19]4)[N:13]=[N:14][C:9]2=[N:8][CH:7]=1)=[CH2:5])C>C(O)(=O)C.Cl>[F:27][C:17]1[C:16]([CH2:15][N:12]2[C:10]3=[N:11][C:6]([C:4](=[O:3])[CH3:5])=[CH:7][N:8]=[C:9]3[N:14]=[N:13]2)=[C:25]([F:26])[CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2
Reactant: C=C(OCC)c1cnc2nnn(Cc3c(F)cc4ncccc4c3F)c2n1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)c1cnc2nnn(Cc3c(F)cc4ncccc4c3F)c2n1
Reaction time: 2 h
Yield: 2.3 %

Procedure:
To a solution of the 6-((6-(1-ethoxyvinyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-5,7-difluoroquinoline (6.0 mg, 0.45 mmol) in acetic acid, 3N HCl (0.1 mL) was added. The solution stirred at it for 2 h. Solvents were removed under reduced pressure. The residue was diluted with water, treated with aqueous NaHCO3 solution, extracted with DCM. The organic layer was washed sequentially with NaHCO3 (aq.) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography with Hexane:ethyl acetate to give yellow solid 1-(1-((5,7-difluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (3.5 mg), yield 63%. LCMS (method B): [MH]+=340.9, tR=2.09 min.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH3:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:22](N(OC)C)=[O:23]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:22]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:23]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CON(C)C(=O)c1ccc(C)c(C)c1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)c2ccc(C)c(C)c2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 3,4-dimethyl-N-methoxy-N-methylbenzamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:46][C@@H:47]([C:59]1[S:60][C:61]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)=[C:62]([C:64]([NH2:66])=[O:65])[N:63]=1)[CH2:48][C:49]1[CH:58]=[CH:57][C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=1>C(Cl)Cl.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10](=[O:12])[NH:46][C@@H:47]([C:59]1[S:60][C:61]([C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)=[C:62]([C:64](=[O:65])[NH2:66])[N:63]=1)[CH2:48][C:49]1[CH:58]=[CH:57][C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=1)[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NC(=O)c1nc([C@H](N)Cc2ccc3ccccc3c2)sc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)c1nc(C(N)=O)c(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 115.5 %

Procedure:
(2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)propionic acid (0.107 g; 0.341 mmol) was dissolved in methylene chloride/dimethyl formamide (5:1; 20 ml). 1-Hydroxybenzotriazole (0.046 g; 0.341 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.071 g; 0.369 mmol) were added. The reaction mixture was stirred 15 min at room temperature and 2-((1R)-1-amino-2-(2-naphthyl)ethyl)-5-phenyl-1,3-thiazole-4-carboxylic acid amide (0.106 g; 0.284 mmol) was added. The reaction mixture was stirred 12 hours at room temperature. The reaction mixture was washed with water (20 ml), sodium hydrogensulfate (10%; 20 ml), sodium hydrogencarbonate (satd; 20 ml), water (20 ml) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (2×15 cm) using ethyl acetate/heptane (2:1) as eluent to afford 0.22 g of ((1R)-1-((1R)-1-(4-carbamoyl-5-phenyl-1,3-thiazole-2-yl)-2-(2-naphthyl)-ethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]([F:13])([F:12])C([O-])=O.[Na+].CN(C=O)C.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][N:22]=1>CCOCC>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:8]([F:12])[F:13])=[CH:23][N:22]=1
Reactant: Oc1ccc(Br)nc1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: FC(F)Oc1ccc(Br)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
Potassium carbonate (2.4 g, 17.3 mmols) and sodium chlorodifluoroacetate (4.2 g, 27.5 mmols) were added to a DMF (20 mL) solution of 2-bromo-5-hydroxypyridine (2.4 g, 13.8 mmols) and stirred overnight at 80° C. The reaction liquid was cooled to room temperature, added ether, washed with water and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the resulting residue was purified on silica gel column chromatography (C-300; hexane:ethyl acetate=100:1-100:2) to provide the title compound (1.32 g, 43%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:18][S:19]([NH:22][CH3:23])(=[O:21])=[O:20])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[H][H]>[OH-].[OH-].[Pd+2]>[CH3:23][NH:22][S:19]([CH2:18][C:4]1[CH:5]=[C:6]2[C:10](=[CH:2][CH:3]=1)[NH:9][CH:8]=[C:7]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17])(=[O:20])=[O:21]
Reactant: CNS(=O)(=O)Cc1cc(Br)c2[nH]cc(C[C@H]3CCCN3C)c2c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Product: CNS(=O)(=O)Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Yield: 58 %

Procedure:
A solution of (R)-7-bromo-5-(methylaminosulfonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(193 g) in industrial methylated spirit (950 mL) containing Pearlman's catalyst (47.6 g total) was exposed to hydrogen gas (50 psi). The catalyst was then filtered through an Arbacel pad, washing with hot industrial methylated spirit (2×100 mL) and the combined filtrate and washings evaporated in vacuo to an organic residue. The filtered solids (catalyst+filter aid) were then reslurried in 2N hydrochloric acid (500 mL) then refiltered (through Arbacel)and the filtrand washed with 2N hydrochloric acid (4×250 mL) and water (2×100 mL). The aqueous filtrate and washes were combined with the organic residue and then once washed with ethyl acetate (1000 mL). The aqueous solution was chilled then made basic by addition of 40% aqueous sodium hydroxide solution precipitating the title compound as a pale-yellow solid. This solid was filtered, washed with water (2×100 mL) and dried in vacuo to give the title compound (89.9 g). TLC (methyl iso-butyl ketone/acetic acid/water 2:1:1 Top phase): Rf=0.23. 1H NMR (d6DMSO) δ 10.85 (s, 1H), 7.5 (s, 1H), 7.3 (d, 1H), 7.15 (s, 1H), 7.05 (d, 1H), 6.8 (q, 1H), 4.35 (s, 2H), 3.0 (m, 2H), 2.55-2.4 (d, 3H and m, 2H), 2.35 (s, 3H), 2.1 (m, 1H), 1.7-1.4 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.[Li]CCCC.C1C[O:22][CH2:21]C1>>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=1[F:13])[CH:21]=[O:22]
Reactant: Fc1ccc(Br)cc1C1OCCO1
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: O=Cc1ccc(F)c(C2OCCO2)c1
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a −78° C. solution of 2-(5-bromo-2-fluoro-phenyl)-[1,3]dioxolane (1.024 g, 4.047 mmol) in THF (40 mL) was added 2.5 M n-BuLi (1.80 mL, 4.45 mmol). After 20 min, the reaction was quenched with DMF (1.60 mL). After stirring for 1 h, the mixture was diluted with DCM, washed with a satd. aq. NaHCO3, dried (MgSO4), and concentrated. Purification by FCC (EtOAc/hexanes) gave the desired product (406.5 mg, 87%) as a white solid. 1H NMR (acetone-d6): 10.05 (s, 1H), 8.17-8.09 (m, 1H), 8.06-7.97 (m, 1H), 7.43-7.33 (m, 1H), 6.10-6.04 (m, 1H), 4.19-4.11 (m, 2H), 4.08-4.00 (m, 2H).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[O:27][CH:26]([CH2:28]O)[N:17]3[C:18]4[CH:19]=[CH:20][CH:21]=[C:22]([F:25])[C:23]=4[CH:24]=[C:16]3[C:15]=2[N:30]=1>C(Cl)Cl.O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[O:27][CH:26]([CH2:28][F:7])[N:17]3[C:18]4[CH:19]=[CH:20][CH:21]=[C:22]([F:25])[C:23]=4[CH:24]=[C:16]3[C:15]=2[N:30]=1
Reactant: OCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: FCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: -78 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
DAST (64 mg, 0.29 mmol) was added to a solution of (2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methanol (60 mg, 0.2 mmol) in CH2Cl2 (0.5 mL) at −78° C. under N2. The mixture was stirred at −78° C. for 1 hour. The mixture was then heated to reflux and stirred for another 3 hours. The mixture was then diluted with water (30 mL) and extracted with CH2Cl2 (15 mL*3). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EtOAc=4:1) to provide 2-chloro-11-fluoro-6-(fluoromethyl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (30 mg, yield: 50.0%). 1H-NMR (CDCl3, 400 MHz) δ 7.29˜7.33 (m, 2H), 7.13˜7.20 (m, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.78˜6.83 (m, 1H), 6.46˜6.51 (m, 1H), 4.35˜4.63 (m, 2H). MS (M+H)+: 307/309.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][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][CH3:28])[CH:7]=[CH:6][C:5]=1[OH:29].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][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][CH3:28])[CH:7]=[CH:6][C:5]=1[O:29][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(O)c(C(=O)OC)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)OC)c1
Yield: 82.3 %

Procedure:
A mixture of 2.5 g (5.95 mmol) of 2-hydroxy-5-(octadecyloxy)benzoic acid methyl ester, 0.78 ml (6.54 mmol) of benzyl bromide and 4.1 g (29.8 mmol) of potassium carbonate in 100 ml of acetone and 10 ml of DMF was stirred at reflux under an argon atmosphere for 24 hours. The solvent was removed at reduced pressure and the residue was treated with water. The product was extracted with ethyl ether and the dried extract was concentrated to a solid which was purified by HPLC using 5% ethyl acetate-hexane to give 2.5 g (82% yield, mp 52°-54°) of 5-(octadecyloxy)-2-(phenylmethoxy)benzoic acid methyl ester.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2[CH:45]=[CH:46][CH:47]=[N:48]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:48][CH:47]5[CH2:45][CH2:46]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Product: COc1cc(C(=O)NC2CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and cyclopropylamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50-0.61 (m, 2 H) 0.70 (dd, J=7.07, 2.27 Hz, 2 H) 1.31-1.48 (m, 2 H) 1.51-1.70 (m, 4 H) 1.71-1.91 (m, 4 H) 2.81 (dt, J=7.14, 3.63 Hz, 1 H) 3.17 (s, 3 H) 3.93 (s, 3 H) 4.03 (q, J=7.07 Hz, 2 H) 4.46 (t, J=11.62 Hz, 1 H) 7.40-7.55 (m, 2 H) 7.90 (s, 1 H) 8.21 (s, 1 H) 8.26 (d, J=8.34 Hz, 1 H) 8.37 (d, J=3.79 Hz, 1 H). [M+H] C25H30F2N6O3 calc'd for, 501; found 501.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([Li])CCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>>[CH2:9]([C:3]1[CH:4]=[CH:5][C:6]([B:24]([OH:29])[OH:25])=[C:7]([F:8])[C:2]=1[F:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCc1cccc(F)c1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: CCCCCCCCCCc1ccc(B(O)O)c(F)c1F

Procedure:
Quantities: compound from Example 27 (26.7 g, 105 mmol), n-butyllithium (11 cm3, 10.0M in hexanes, 0.11 mol) and triisopropyl borate (39.5 g, 0.21 mol). The experimental procedure was as described in Example 28.