Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Br)C(C1C=CC=CC=1)=O.C1OC1C1C=CC=CC=1.[CH3:20][C:21]([C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=1)=[O:22].CCOC(C)=O>C(Cl)(Cl)Cl>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([Cl:29])[CH:26]=1)[CH:21]1[O:22][CH2:20]1
Reactant: CC(=O)c1cc(Cl)cc(Cl)c1
Agent: O=C(CBr)c1ccccc1
Agent: c1ccc(C2CO2)cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Clc1cc(Cl)cc(C2CO2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The phenacyl bromide intermediate for the above-mentioned styrene oxide is prepared by brominating 10 g of 3,5-dichloroacetophenone in 50 ml of CHCl3 /50 ml of EtOAc with 23.6 g of CuBr2. The mixture is heated at reflux for 2.5 hours and cooled to room temperature. After stirring for 16 hours at room temperature, the mixture is cooled in ice for 2 hours and filtered. The filter cake is washed with 50 ml of CHCl3 and the combined filtrates are twice decolorized with activated carbon, filtered, and evaporated to dryness in vacuo to afford the orange oil of the 3,5-dichlorostyrene oxide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[N:27]([C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[C:32]([O:34][CH3:35])=[O:33])=[C:28]=[O:29]>O1CCOCC1>[CH3:35][O:34][C:32](=[O:33])[C:31]1[CH:36]=[CH:37][CH:38]=[CH:39][C:30]=1[NH:27][C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])[CH:7]=1)=[O:29]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: COC(=O)c1ccccc1N=C=O
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1NC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxan (0.5 mL) and methyl 2-isocyanatobenzoate (0.021 mL, 0.12 mmol) was added. The solution was stirred at 50° C. for 24 h. Methyl 2-isocyanatobenzoate (0.01 mL, 0.06 mmol) was added. The solution was stirred at 50° C. for 24 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 10:90→40:60 as the eluent. This afforded the title compound as yellow oil. 13C NMR (CDCl3) δ 195.8, 169.0, 159.0 (dd), 155.4 (dd), 152.4, 147.6, 142.5, 139.5, 135.6, 135.1, 134.6, 133.6, 133.4, 132.1, 130.8, 129.4, 124.5 (dd), 124.1 (dd), 123.3, 121.7, 121.3, 119.8, 116.3, 114.3, 112.8, 111.5 (dd), 104.9 (dd), 52.2, 19.8
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[OH:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[O:20][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1F

Procedure:
In a similar manner to Example 2, starting material step (b), t-butyl bromoacetate (5.6 ml), 2-fluoro-4-nitrophenol (5 g), anhydrous potassium carbonate (5.3 g) and acetone (200 ml) were reacted to give t-butyl 2-fluoro-4-nitrophenoxyacetate (8.3 g) as an off-white solid: m.p. 62°-64° C.; NMR Spectrum (DMSO-d6) 1.49 (9H, s), 4.70 (2H, s), 6.94 (1H, m), 8.01 (2H, m); Mass Spectrum m/Z 272 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH2:26][CH2:27][N:28]=4)=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[O-2].[Ca+2].[H][H]>[Pd].CO>[O:25]1[CH2:26][CH2:27][N:28]=[C:24]1[C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:5]3[N:4]=[N:3][CH:2]=[CH:7][CH:6]=3)[CH2:13][CH2:12]2)=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: Clc1ccc(N2CCN(CCCOc3ccc(C4=NCCO4)cc3)CC2)nn1
Agent: [Pd]
Agent: [Ca+2]
Agent: [O-2]
Solvent: CO
Product: c1cnnc(N2CCN(CCCOc3ccc(C4=NCCO4)cc3)CC2)c1
Yield: 17.2 %

Procedure:
A mixture of 3.8 parts of 3-chloro-6-[4-[3-[4-(4,5-dihydro-2-oxazolyl)phenoxy]-propyl]-1-piperazinyl]pyridazine, 200 parts of methanol and 2 parts of calcium oxide was hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off, washed with 2-propanol and 2,2'-oxybispropane and dried over weekend at 60° C., yielding 0.7 parts (17.2%) of 3-[4-[3-[4-(4,5-dihydro-2 -oxazolyl)phenoxy]propyl]-1-piperazinyl]pyridazine; mp. 144.7° C. (comp. 169).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([NH:28][C:29](=[O:32])[CH2:30][OH:31])[C@@H:25]([OH:33])[C@H:24]3[OH:34])=[C:16]([NH:35][CH2:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:15]=2)[CH2:10]1.Cl[C:51](OC1C=CC=CC=1)=[O:52].[OH:60][C:61]1[CH:62]=[C:63]([CH:66]=[CH:67][CH:68]=1)[CH2:64][NH2:65]>CN1C(=O)CCC1.CO>[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4].[C:44]1([CH:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:36][NH:35][C:16]2[N:15]=[C:14]([N:11]3[CH2:12][CH2:13][C@@H:9]([NH:8][C:51]([NH:65][CH2:64][C:63]4[CH:66]=[CH:67][CH:68]=[C:61]([OH:60])[CH:62]=4)=[O:52])[CH2:10]3)[N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[C@@H:23]2[CH2:27][C@H:26]([NH:28][C:29](=[O:32])[CH2:30][OH:31])[C@@H:25]([OH:33])[C@H:24]2[OH:34])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)C1
Reactant: NCc1cccc(O)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)NCc5cccc(O)c5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide trifluoroacetate (Example 1) (1.1 g, 2 mmol) in NMP (2 ml) and MeOH (10 ml) is added dropwise phenyl chloroformate (0.47 g, 3 mmol). The reaction mixture is allowed to stir at room temperature for 3 hours and then treated with 3-hydroxybenzylamine (0.55 g, 4.45 mmol) and stirred for a further 2 hours at 80° C. Purification of the product by C-18 reverse phase column chromatography eluting with acetonitrile:water:TFA (0.1%) (gradient of 0 to 100% acetonitrile) yields the title compound. (MH+ 722.31)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:38]2[CH:42]=[N:41][N:40]=[N:39]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([N:12]2[C@H:21]([C:22]([NH:24][C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=3)=[O:23])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])[CH:7]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:38]2[CH:42]=[N:41][N:40]=[N:39]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([N:12]2[C@H:21]([C:22]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:36][CH:37]=3)=[O:23])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)/C=C/c2cc(Cl)ccc2-n2cnnn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)/C=C/c2cc(Cl)ccc2-n2cnnn2)cc1

Procedure:
(S,E)-tert-Butyl 4-(2-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)benzoate: To 1B (0.1 g, 0.284 mmol) and Intermediate 1 (0.099 g, 0.284 mmol) in DMF (2 ml) was added DIEA (0.149 ml, 0.851 mmol). The reaction was quenched with H2O (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with H2O (10 mL), brine (10 mL) and dried (MgSO4). Purified by normal phase chromatography to afford 0.15 g of desired product as yellow solid. MS (ESI) m/z: 585.2 (M+H)+. (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:7][CH:6]1[C:8]([OH:10])=O)=[O:4].O1CCCC1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:23][C:24]1[N:25]=[C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([CH3:49])=[C:37]([NH:39][C:40]([C:42]4[N:46]([CH3:47])[N:45]=[C:44]([CH3:48])[CH:43]=4)=[O:41])[CH:38]=3)=[N:28][N:27]2[CH:50]=1>CN(C)C=O.CN(C)C(=O)C>[CH3:47][N:46]1[C:42]([C:40]([NH:39][C:37]2[CH:38]=[C:33]([CH:34]=[CH:35][C:36]=2[CH3:49])[O:32][C:29]2[CH:30]=[CH:31][C:26]3[N:27]([CH:50]=[C:24]([NH:23][C:8]([CH:6]4[CH2:7][CH:5]4[C:3]([O:2][CH3:1])=[O:4])=[O:10])[N:25]=3)[N:28]=2)=[O:41])=[CH:43][C:44]([CH3:48])=[N:45]1
Reactant: COC(=O)C1CC1C(=O)O
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COC(=O)C1CC1C(=O)Nc1cn2nc(Oc3ccc(C)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Yield: 24.8 %

Procedure:
In the same manner as in Example 279 and using 2-(methoxycarbonyl)cyclopropanecarboxylic acid (140 mg, 0.78 mmol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (69 μL, 0.8 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (250 mg, 0.6 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (75 mg, 25%) was obtained as a white solid.
Reaction SMILES: C1(NC(C2C3C=C(C4C(F)=CN=C(NCCCC5CCNCC5)N=4)SC=3C=CC=2)=O)CC1.[ClH:33].Cl.[CH:35]1([NH:38][C:39]([C:41]2[C:49]3[CH:48]=[C:47]([C:50]4[C:55](F)=[CH:54][N:53]=[C:52]([NH:57][CH2:58][CH2:59][CH2:60][CH:61]5[CH2:66][CH2:65][N:64]([CH3:67])[CH2:63][CH2:62]5)[N:51]=4)[S:46][C:45]=3[CH:44]=[CH:43][CH:42]=2)=[O:40])CC1.CNC(C1C2C=C(C3C([Cl:87])=CN=C(Cl)N=3)SC=2C=CC=1)=O>>[ClH:87].[ClH:33].[CH3:35][NH:38][C:39]([C:41]1[C:49]2[CH:48]=[C:47]([C:50]3[C:55]([Cl:87])=[CH:54][N:53]=[C:52]([NH:57][CH2:58][CH2:59][CH2:60][CH:61]4[CH2:66][CH2:65][N:64]([CH3:67])[CH2:63][CH2:62]4)[N:51]=3)[S:46][C:45]=2[CH:44]=[CH:43][CH:42]=1)=[O:40]
Reactant: CN1CCC(CCCNc2ncc(F)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reactant: CNC(=O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Agent: Cl
Agent: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3F)cc12
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCC4CCN(C)CC4)ncc3Cl)cc12

Procedure:
Using the methods of 2-[5-fluoro-2-(3-piperidin-4-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and 2-{5-fluoro-2-[3-(1-methylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 458 (35Cl) and 460 (37Cl) [M(free base)+H].
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.C=O.[CH2:12](N(CC)CC)C.[C:19]1([CH3:39])[CH:24]=[CH:23][C:22]([S:25]([O:28]S(C2C=CC(C)=CC=2)(=O)=O)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>N12CCCN=C1CCCCC2.C(OCC)(=O)C.O1CCCC1>[CH3:39][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:28][CH2:12][N:5]2[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: CCN(CC)CC
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCn2cc(C(F)(F)F)cn2)cc1

Procedure:
To a tetrahydrofuran solution (2 mL) of 4-(trifluoromethyl)-1H-pyrazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (10.9 μL, 0.07 mmol) and paraformaldehyde (43.8 mg, 1.46 mmol) were added at room temperature and the resultant mixture was stirred at 60° C. for 12 hours and at room temperature for 1 day. The reaction solution was filtered and triethylamine (153 μL, 1.10 mmol) and p-toluenesulfonic acid anhydride (286 mg, 0.88 mmol) were added to the filtrate, following by stirring the resultant mixture for 30 minutes. After completion of the reaction, saturated sodium carbonate aqueous solution was added to the reaction solution and extraction with ethyl acetate from the resultant mixture was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the obtained residue, ethyl acetate was added and the resultant mixture was filtered and concentrated under reduced pressure to obtain a crude product (232 mg) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.N1([CH2:26][OH:27])C2C=CC=CC=2N=N1.[Li+].CC([N-]C(C)C)C>>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([N:9]2[CH2:10][CH2:11][S:12](=[O:15])(=[O:16])[CH2:13][CH2:14]2)[CH2:26][OH:27])[CH:5]=[CH:4][CH:3]=1
Reactant: OCn1nnc2ccccc21
Reactant: O=S1(=O)CCN(Cc2cccc(Br)n2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=S1(=O)CCN(C(CO)c2cccc(Br)n2)CC1

Procedure:
The title compound was prepared as described in Example 3, Step 1 using 4-[(6-bromopyridin-2-yl)methyl]thiomorpholine 1,1-dioxide (2.94 g, 9.63 mmol), 1H-1,2,3-benzotriazol-1-ylmethanol (2.87, 19.17 mmol), and LDA (16 mL of 1.8 M in tetrahydrofuran/heptane/ethylbenzene) as starting materials. LRMS (APCI) calcd for C11H16BrN2O3S [M+H]+: 335.0, Found: 334.9.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.C1C(=O)N([Br:28])C(=O)C1>ClCCl>[Br:28][C:17]1[CH:18]=[CH:19][C:20]2[N:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: COCCOCCn1c2ccccc2c2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COCCOCCn1c2ccccc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a solution of 1a (2 g, 7.4 mmol) in dichloromethane (60 mL) was added NBS (1.3 g, 7.4 mmol) portionwise in an ice-water bath. After complete addition, the solution mixture was warmed to room temperature and stirred overnight. The resulting solution was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by silica gel chromatography using ethyl acetate and petroleum ether (EA:PE=1:5) as eluent to afford 2a (1.75 g) in 68% yield as an oil that can turn into solid after standing. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=2.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.51 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.44 (m, 2H), 7.34 (d, J=8.4 Hz, 1H), 7.22 (m, 1H), 4.46 (t, J=6.0 Hz, 2H), 3.83 (t, J=6.0 Hz, 2H), 3.48 (m, 2H), 3.39 (m, 2H), 3.28 (s, 3H). 13C NMR (400 MHz, CDCl3) δ 140.7, 139.2, 128.2, 126.3, 124.5, 122.8, 121.8, 120.4, 119.3, 111.7, 110.4, 109.0, 71.8, 70.7, 69.1, 59.0, 43.2. MS (FAB) m/z Calcd for C17H18BrNO2 347.0. Found 347.3 [M]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O-:8])=[C:4]([Br:9])[C:3]=1[Br:10].[N:11]1[C:18](Cl)=[N:17][C:15](Cl)=[N:14][C:12]=1Cl.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Br:28])[C:22]=1[Br:29].[Cl-]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[N:14]=[C:15]([O:27][C:24]3[CH:25]=[CH:26][C:21]([Br:20])=[C:22]([Br:29])[C:23]=3[Br:28])[N:17]=[C:18]([O:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([Br:10])[C:4]=3[Br:9])[N:11]=2)=[C:4]([Br:9])[C:3]=1[Br:10]
Reactant: [O-]c1ccc(Br)c(Br)c1Br
Reactant: Oc1ccc(Br)c(Br)c1Br
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Cl-]
Product: Brc1ccc(Oc2nc(Oc3ccc(Br)c(Br)c3Br)nc(Oc3ccc(Br)c(Br)c3Br)n2)c(Br)c1Br

Procedure:
An exemplary production process according to this invention comprises preparing an aqueous tribromophenolate solution and dripping this aqueous solution to a dispersion or solution of cyanuric chloride and tertiary amine in a non-hydrophilic solvent or adding said tertiary amine and a powder of cyanuric chloride to said aqueous solution. The preferred molar ratio of cyanuric chloride to tribromophenol is 1:2.94-3.60. Where both a tertiary amine and a phase transfer catalyst are employed, an exemplary procedure comprises preparing an aqueous tribromophenolate solution, adding a tertiary amine thereto and dripping the mixture to a solution or dispersion of cyarnuric chloride and phase transfer catalyst in a non-hydrophilic solvent or adding said phase transfer catalyst, said tertiary amine and a powder of cyanuric chloride to the aqueous tribromophenolate solution. After the above dripping or addition, the reaction system is aged where necessary and the non-hydrophilic solvent is removed from the reaction system at atmospheric or subatmospheric pressure. In this manner, tris(tribromophenoxy)-s-triazine of high purity can be obtained.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][C:3]1=[O:12].[Cl-].[NH4+].CO.C(Cl)Cl>C1COCC1.[Zn]>[Cl:11][C:9]1[C:10]2[CH2:2][C:3](=[O:12])[NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=C1Nc2ncnc(Cl)c2C1(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: O=C1Cc2c(Cl)ncnc2N1
Reaction time: 0.33 h
Yield: 378.4 %

Procedure:
Add zinc (2 equiv; 12.12 mmol; 792 mg) to a suspension of 5,5-dibromo-4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (6.06 mmol; 1.98 g) in THF (20 mL) and add saturated ammonium chloride aqueous (3 mL) at 20° C. (exothermic). Stir 20 min then filter through Celite®, rinse with THF, wash the organic phase twice with saturated ammonium chloride. Extract combined aqueous layers four times with 100 mL 1:1 THF:EA, wash the combined organic phases with saturated ammonium chloride, dry over MgSO4, filter through silica gel plug, rinse with 1 L 5% MeOH/DCM and evaporate filtrates. Suspend crude solid in refluxing mixtures of DCM/EA and load onto 330 g of dry silica gel. Chromatograph with 0 to 2% MeOH/DCM to provide the title compound 3.89 g (22.93 mmol; 59%). MS (ES+): m/z=168 (M−H).
Reaction SMILES: CO[N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([O:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[CH:6]=1.C(=O)=O.C(O)(=O)C.[H][H]>C(O)C.O1CCCC1.[Pd]>[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([O:14][Si:15]([CH:19]([CH3:21])[CH3:20])([CH:22]([CH3:24])[CH3:23])[CH:16]([CH3:17])[CH3:18])[CH:6]=1
Reactant: CON=Cc1ccc([N+](=O)[O-])c(O[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)[Si](Oc1cc(CN)ccc1N)(C(C)C)C(C)C

Procedure:
A solution of 4-nitro-3-[(triisopropylsilyl)oxy]benzaldehyde O-methyloxime (3.1 g, 9.8 mmol) in ethanol (100 mL) and tetrahydrofuran (80 mL) is degassed with solid carbon dioxide, then charged with 10% palladium on carbon (200 mg) and glacial acetic acid (1.3 mL). The mixture is shaked under 45 psi hydrogen gas for 36 hours. The mixture is then filtered through a pad of diatomaceous earth, and the filtrate is concentrated under reduced pressure to give {4-(aminomethyl)-2-[(triisopropylsilyl)oxy]phenyl}amine, a golden semi-solid, as its diacetic acid salt. This material is used in the subsequent step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH2:37])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]2(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:46]1([S:52](Cl)(=[O:54])=[O:53])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CC#N>[C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:37][S:52]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(=[O:54])=[O:53])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]2(=[O:27])=[O:28])=[C:11]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-amino-3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid tert-butyl ester (Example 132, step C) (10 mg, 0.249 mmol) and triethylamine (51 mg, 0.5 mmol) in MeCN (5 mL) is added benzenesulfonyl chloride (44 mg, 0.249 mmol) and the mixture is stirred at RT for 2 h. The solvent is removed under reduced pressure and the residue partitioned between methylene chloride and 1N HCl. The organic phase dried over sodium sulfate and the solvent removed under reduced pressure. The residue is purified by flash chromatography using a gradient of 0-40% EtOAc/hexane as eluent to give the title compound: (M−1)−=700.
Reaction SMILES: [S:1]([N:11]1[CH2:20][C:19](=O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:22]([O:24][P:25]([C:30]([P:32](=[O:39])([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])=[CH2:31])(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23].C1CCN2C(=NCCC2)CC1.C1C[O:54]CC1>C(OCC)(=O)C>[CH2:37]([O:36][P:32]([CH:30]([P:25](=[O:29])([O:26][CH2:27][CH3:28])[O:24][CH2:22][CH3:23])[CH2:31][CH:19]1[C:18](=[O:54])[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:11]([S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:3])=[O:2])[CH2:20]1)(=[O:39])[O:33][CH2:34][CH3:35])[CH3:38]
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)N2CC(=O)c3ccccc3C2)cc1
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(CC1CN(S(=O)(=O)c2ccc(C)cc2)c2ccccc2C1=O)P(=O)(OCC)OCC

Procedure:
The ketone (II, 4.27 g), ethenylidenebisphosphonic acid tetraethyl ester (I, 3.60 g) and DBU (2 ml) are stirred in THF (30 ml) for 1 hour. The reaction is diluted with ethyl acetate, washed with hydrochloric acid (1 N), saturated sodium bicarbonate, and saline, dried with magnesium sulfate, and concentrated under reduced pressure. The product is chromatographed eluting with ethyl acetate/ethyl acetate-acetone 1/1) to give the title compound, MS (m/e) 601, 446, 400, 372 and 155; IR (neat) 2983, 1689, 1599, 1574, 1494, 1477, 1392 and 1254 cm-1 ; NMR (CDCl3) 7.95, 7.8, 7.7, 7.49, 7.28, 7.14, 4.47, 4.20, 3.79, 3.14, 2.83, 2.4, 1.93 and 1.32 δ.
Reaction SMILES: O[CH:2]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1.P(Cl)(Cl)[Cl:15].C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[Cl:15][CH:2]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: COc1ccc2c(c1)C(O)CCO2
Reactant: ClP(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(Cl)CCO2
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of 4-hydroxy-6-methoxy-2,3-dihydro-4H-1-benzopyran (20 g) dissolved in benzene (150 ml), phosphorus trichloride (16.7 g) diluted in benzene (50 ml) is cautiously added under stirring at a temperature maintained below 20° C. by external cooling, then the reaction mixture is kept at 50° C. for 1 hour. After cooling the solution is poured into a 10% NaHCO3 solution (1 l) containing ice, under stirring, then the organic phase is separated and the aqueous phase extracted with ethyl acetate. The organic solutions are evaporated to dryness in vacuo to yield crude 4-chloro-6-methoxy-2,3-dihydro-4H-1-benzopyran as brown oil (21.5 g), which is dissolved in anhydrous dimethylformamide (90 ml) and added under stirring at about 20° C. to a solution of diethylmalonate carbanion (prepared from 19.1 g of diethylmalonate and 5.7 g of 50% sodium hydride) in anhydrous dimethylformamide (30 ml). The reaction mixture is heated at 70° C. for 7 hours, then is cooled at room temperature and diluted with ice water containing excess NaH2PO4.