Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[S:31](Cl)(=[O:33])=[O:32])[CH:24]=[CH:23][CH:22]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[S:31]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)(=[O:33])=[O:32])[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc2cccnc12)N1CCNCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 22.1 %

Procedure:
1-tert-Butoxycarbonylpiperazine (2.22 g) and triethylamine (2.0 mL) were dissolved in dichloromethane (100 mL), and 8-quinolinesulfonyl chloride (2.71 g) was added thereto. The mixture was stirred at room temperature for 14 hr. 10% citric acid solution was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with brine, dried and concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (5 mL) was added thereto. The mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium hydrogencarbonate solution was added to the residue. The mixture was extracted with chloroform, and the extract was dried and concentrated under reduced pressure to give 1-(8-quinolinesulfonyl)piperazine (0.73 g) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:14][O-:15].[Na+].[CH3:17]O>>[CH3:17][O:8][CH:7]([O:15][CH3:14])[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: CO
Reactant: O=Cc1ccncc1
Reactant: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(OC)c1ccncc1

Procedure:
80 g (74.6 mmoles) of pyridine-4-carboxaldehyde is dissolved in 150 mL of methanol. 123.5 mL (112 mmoles) of trimethyl orthoformiate is added to the reaction mixture at room temperature followed by the addition of 33 mL of concentrated sulfuric acid. The reaction mixture is kept under reflux for 24 hours and once cooled, added to 300 mL of sodium methylate solution. The white suspension obtained is filtered over celite, the filtrate is concentrated under vacuum and 70.3 g of 4-dimethoxymethyl-pyridine is obtained as a yellow oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14])(=[O:3])[CH3:2].[N+](=[CH2:18])=[N-].[BrH:19]>CCOCC>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:14])[CH2:18][Br:19])(=[O:3])[CH3:2]
Reactant: Br
Reactant: CC(=O)OCCCCCCCCC(=O)Cl
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CC(=O)OCCCCCCCCC(=O)CBr

Procedure:
9-Acetoxynonanoyl chloride (4.0 g, 17 mmol) was slowly added to a solution of diazomethane (40 mmol) in ether (100 ml) at 0° C. After 1 h at 0° C. concentrated hydrobromic acid (20 ml) was added. After 1 h at 20° C. the ether was separated, dried (MgSO4), and evaporated under reduced pressure to give 10-bromo-9-oxodecyl acetate as a yellow oil (4.4 g 88%); δH (CDCl3) 4.0(2H, t, O), 3.8(2H, s, CH2Br), 2.6(2H, t, CH2CO), 2.0(3H, s, OAC), 1.1-1.8(12H, m, (CH2)6).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[C:26]([CH3:28])[C:5]([O:6][C:7]2[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([CH3:16])[N:10]=[C:9]([NH:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[N:8]=2)=[C:4]([CH3:29])[CH:3]=1.C(O[CH:35](N(C)C)[N:36]([CH3:38])[CH3:37])(C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:27]=[C:26]([CH3:28])[C:5]([O:6][C:7]2[C:12]([N+:13]([O-:15])=[O:14])=[C:11](/[CH:16]=[CH:35]/[N:36]([CH3:38])[CH3:37])[N:10]=[C:9]([NH:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[N:8]=2)=[C:4]([CH3:29])[CH:3]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cc(Br)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(C)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(/C=C/N(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a homogenous mixture of 4-(4-(4-bromo-2,6-dimethylphenoxy)-6-methyl-5-nitropyrimidin-2-ylamino)benzonitrile (22.71 g, 50 mmol) in DMF (300 ml) was added tert-butoxybis(dimethylamino) methane (12.39 ml, 60 mmol) over 15 minutes. The mixture was stirred at room temperature overnight. DMF was partially removed. The residue was washed with water and extracted with ethyl acetate (×3). The organic layers were combined, washed with brine, dried (MgSO4) and concentrated to dryness yielding to the desired product as a yellow solid (23.41 g, 46.0 mmol, 92%) which was used in next step without further purification. 1H NMR (CDCl3, 400 MHz) δ2.14 (s, 6H), 2.98 (bs, 3H), 3.13 (bs, 3H), 5.54 (d, J=12.4 Hz, 1H), 7.03 (s, 1H), 7.27 (d, J=8.6, 2H), 7.28 (s, 2H), 7.40 (d, J=8.6, 2H), 8.03 (d, J=12.2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]=[CH2:14])=[CH:8][C:7]=1[O:15][CH3:16])[CH:2]1[O:4][CH2:3]1.C([O-])([O-])=[O:18].[Na+].[Na+]>O>[CH2:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH:2]([OH:4])[CH2:3][OH:18])=[C:7]([O:15][CH3:16])[CH:8]=1)[CH:13]=[CH2:14]
Reactant: C=CCc1ccc(OCC2CO2)c(OC)c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=CCc1ccc(OCC(O)CO)c(OC)c1
Temperature: 80 °C
Yield: 97 %

Procedure:
A 3,000 mL, 3-necked, round-bottom flask was equipped with a mechanical stirrer, a reflux condenser and a 250 mL addition funnel. The flask was charged with H2O (1,500 mL) and 70% HClO4 (1 mL) and heated to ca. 80° C. while stirring vigorously (ca. 750 rpm). 4-Allyl-2-methoxyphenyl glycidyl ether was placed in the addition funnel and was added dropwise to the reaction mixture over a 4-5 hour period. The reaction mixture was stirred for 48 hours at ca. 80° C. The mixture was then allowed to cool and was neutralized with 5% Na2CO3. The phases were separated and the aqueous phase extracted with CH2Cl2 (1,500 mL). The CH2Cl2 and H2 were removed from the 3-(4-allyl-2-methoxyphenoxy)-1,2-propanediol, i.e., ##STR23## by evaporation in vacuo to yield a pale amber oil (355 g, 97%) which crystallized on standing; mp 77°-79° C. (recrystallized from benzend).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[C:5]#N.[OH-:12].[Na+].C[OH:15]>Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[C:5]([OH:15])=[O:12]
Reactant: COc1cc(Br)cc(C#N)c1
Reactant: [OH-]
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: COc1cc(Br)cc(C(=O)O)c1

Procedure:
The product from step (i) (5.10 g) was dissolved in methanol (20 ml) and 6N NaOH (20 ml) and heated to reflux for 6 h. The mixture was diluted with 2M HCl, extracted with ethyl acetate, dried (MgSO4) and evaporated under reduced pressure to give a white solid (5.10 g).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@H:4]([C:12]([OH:14])=O)[NH:3]1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.Cl.Cl.[NH2:40][C@H:41]([C:48]([N:50]1[C@H:54]([C:55]([NH2:57])=[O:56])[CH2:53][S:52][CH2:51]1)=[O:49])[CH2:42][C:43]1[N:47]=[CH:46][NH:45][CH:44]=1.C(N(CC)CC)C>CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@H:4]([C:12]([NH:40][C@H:41]([C:48]([N:50]2[C@H:54]([C:55]([NH2:57])=[O:56])[CH2:53][S:52][CH2:51]2)=[O:49])[CH2:42][C:43]2[N:47]=[CH:46][NH:45][CH:44]=2)=[O:14])[NH:3]1
Reactant: NC(=O)[C@@H]1CSCN1C(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=C1N[C@H](C(=O)O)Cc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)[C@@H]1CSCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1Cc2ccccc2C(=O)N1
Reaction time: 1.5 h
Yield: 43.9 %

Procedure:
Separately, (3S)-1-oxo-1,2,3,4-tetrahyroisoquinoline-3-carboxylic acid (70 mg, 0.36 mmole) and N-hydroxysuccinimide (41 mg, 0.36 mmole) are dissolved in DMF (5 ml) and thereto is added DCC (74 mg, 0.36 mmole) under ice-cooling. The mixture is stirred for 1.5 hours. To the solution of the activated ester thus prepared are added the (4R)-3-(L-histidyl)-thiazolidine-4-carboxamide dihydrochloride (150 mg, 0.4 mmole) prepared above and triethylamine (0.21 ml, 0.8 mmole) under ice-cooling. The mixture is stirred at 8° C. for 24 hours. The precipitated DCU is filtered off, and the filtrate is concentrated under reduced pressure. The residue is dissolved in water, and the solution is adjusted to pH 8 with sodium bicarbonate and is passed through a column (2.3×26 cm) packed with CHP-20P resin. The column is washed with water (500 ml) and further with 30% methanol (one liter), and then the product is eluted with 50% methanol. The fractions being positive to Pauly reagent are collected, distilled to remove methanol, and then lyophilized to give (4R)-3-{Nα -[(3S)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carbonyl]-L-histidyl}-thiazolidine-4-carboxamide (70 mg, yield: 41.8%).
Reaction SMILES: Cl[C:2]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[CH:3][CH:4]=O.[NH2:12][C:13]1[C:17]([C:18]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[O:19])=[CH:16][NH:15][N:14]=1>C(O)(=O)C>[O:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[C:18]([C:17]1[CH:16]=[N:15][N:14]2[C:2]([C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)=[CH:3][CH:4]=[N:12][C:13]=12)=[O:19]
Reactant: Nc1n[nH]cc1C(=O)c1ccco1
Reactant: O=CC=C(Cl)c1cccnc1
Solvent: CC(=O)O
Product: O=C(c1ccco1)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 0.02 mole of 3-chloro-3-(3-pyridinyl)-2-propenal and 0.02 mole of (3-amino-1H-pyrazol-4-yl)-2-furanyl-methanone in 30 ml of glacial acetic acid was refluxed for 5 hours. The solvent was removed in vacuo and the residue partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The dichloromethane layer was dried over sodium sulfate and passed through a short pad of hydrous magnesium silicate. The eluent was concentrated and the residue crystallized from dichloromethane:hexane to give the desired product as crystals, mp 228°-229° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:24][O:25][C:26](=[O:32])[CH2:27][C@@H:28]([NH2:31])[CH2:29][CH3:30]>N1C=CC=CC=1>[CH3:24][O:25][C:26](=[O:32])[CH2:27][C@@H:28]([NH:31][C:8]([C:3]1[C:2]([NH2:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10])[CH2:29][CH3:30]
Reactant: CC[C@H](N)CC(=O)OC
Reactant: Nc1cccnc1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Product: CC[C@@H](CC(=O)OC)NC(=O)c1ncccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of 321 mg of 3-aminopyridine-2-carboxylic acid in pyridine (5.0 mL) is added 377 mg of 1,1′-carbonyldiimidazole and the mixture is stirred for 2 h at room temperature. The resulting mixture is treated with 300 mg of (S)-3-aminopentanoic acid methyl ester hydrochloride and the mixture is stirred for 16 h at room temperature. Then the solvent is removed under vacuum and the residue is purified by flash chromatography on silica gel to give 250 mg (56%) of (S)-3-[(3-amino-pyridine-2-carbonyl)-amino]-pentanoic acid methyl ester.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]3[O:29][C:30]([CH3:33])=[N:31][N:32]=3)[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[ClH:17].[C:1]1([S:7]([C:10]2[CH:16]=[CH:15][C:13]([NH:14][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]5[O:29][C:30]([CH3:33])=[N:31][N:32]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:12][CH:11]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: Cc1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Product: Cc1nnc(-c2ccc3ncnc(Nc4ccc(S(=O)(=O)c5ccccc5)cc4)c3c2)o1
Product: Cl

Procedure:
The title compound was prepared according to Procedure A from 4-benzenesulphonylaniline and 4-chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.63(1H,bs), 9.42(1H,s), 8.95(1H,s), 8.56(1H,d), 8.10(6H,m), 7.70(4H,m), 2.65(3H,s); m/z (M+1+) 444.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:48]=[CH:47][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:46]=[CH:45][C:28]([C:29]([NH:31][CH2:32][C:33]([CH3:44])([CH3:43])[CH2:34][NH:35]C(=O)OC(C)(C)C)=[O:30])=[CH:27][N:26]=3)[CH:13]=2)=[CH:8][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:35][CH2:34][C:33]([CH3:44])([CH3:43])[CH2:32][NH:31][C:29](=[O:30])[C:28]1[CH:45]=[CH:46][C:25]([NH:24][C:14]2[CH:13]=[C:12]([NH:11][CH2:10][C:9]3[CH:47]=[CH:48][C:6]([O:5][CH2:4][CH2:3][CH2:2][Br:1])=[CH:7][CH:8]=3)[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=2)=[N:26][CH:27]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2cc(NCc3ccc(OCCCBr)cc3)nc(OCC(F)(F)F)n2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CN)CNC(=O)c1ccc(Nc2cc(NCc3ccc(OCCCBr)cc3)nc(OCC(F)(F)F)n2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of tert-butyl (3-(6-((6-((4-(3-bromopropoxy)benzyl)amino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)nicotinamido)-2,2-dimethylpropyl)carbamate (10 mg) in DCM (3 mL) was added TFA (0.3 ml). The mixture was stirred at room temperature for 3 hours. All the solvents were removed under vacuum to give N-(3-amino-2,2-dimethylpropyl)-6-(6-(4-(3-bromopropoxy)benzylamino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-ylamino)nicotinamide (8 mg).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]1[NH:21][C:20]2[CH:19]=[C:18]3[C:14]([CH:15]=[N:16][NH:17]3)=[CH:13][C:12]=2[N:11]=1.Cl.[NH2:23][CH2:24][C@H:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([Br:35])[CH:28]=1)[OH:26].CN1CCOCC1>C(#N)C>[Br:35][C:29]1[CH:28]=[C:27]([C@H:25]([OH:26])[CH2:24][NH:23][C:3]2[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=2[C:10]2[NH:21][C:20]3[CH:19]=[C:18]4[C:14]([CH:15]=[N:16][NH:17]4)=[CH:13][C:12]=3[N:11]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH3:34]
Reactant: COc1ccc([C@H](O)CN)cc1Br
Reactant: O=c1[nH]ccc(Cl)c1-c1nc2cc3cn[nH]c3cc2[nH]1
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COc1ccc([C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4cn[nH]c4cc3[nH]2)cc1Br
Temperature: 80 °C
Yield: 63.8 %

Procedure:
The mixture of crude 4-chloro-3-(1,7-dihydro-1,2,5,7-tetraaza-s-indacen-6-yl)-1H-pyridin-2-one hydrochloric acid salt (80 mg, 0.25 mmol), (S)-2-amino-1-(3-bromo-4-methoxy-phenyl)-ethanol hydrochloric acid salt (105 mg, 0.37 mmol), N-methyl morpholine (0.5 ml, excess), and acetonitrile (15 mL) was heated to 80° C. overnight and cooled to room temperature. After concentration in vacuo, the residue was purified by prep. HPLC to yield the titled compound (79 mg, 66%). 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.85 (s, 1H), 7.69 (narrow d, J=2.0 Hz, 1H), 7.59 (s, 1H), 7.40 (dd, J=2.0, 8.5 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 6.96 (d, J=8.5 Hz, 1H), 6.22 (d, J=7.6 Hz, 1H), 4.93 (m, 1H), 3.80 (s, 3H), 3.66 (d, J=6.0 Hz, 2H). LCMS (t=1.39 min), [M+H]+ 495.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>O.ClCCl>[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:15])=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
A photochromic initiator (represented by structure 1.31 in Table 1 above) was prepared as follows. Step 1: Anisole (27.5 grams), 4-fluorobenzoyl chloride (35 grams) and dichloromethane (250 mL) were combined in a reaction flask. Aluminum chloride (30.8 grams) was added to the reaction mixture slowly over 20 minutes. Stirred the reaction mixture at room temperature for two hours and then poured it into a mixture of 70 mL concentrated hydrochloric acid and 500 mL of water. The layers were phase separated and the aqueous layer was extracted with two portions of dichloromethane (300 mL each). The organic portions were combined and washed with saturated aqueous sodium bicarbonate (400 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to yield 48.0 grams of 4-fluoro-4′-methoxy-benzophenone as a white solid. This material was not purified further but was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8](Br)[CH2:9][F:10])[N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:9][F:10])[CH:5]=[CH:6][CH:7]=1
Reactant: FCC(Br)c1cccc(Br)n1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: FCC(c1cccc(Br)n1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-6-(1-bromo-2-fluoroethyl)pyridine (70 mg, 0.25 mmol), morpholine (0.022 mL, 0.25 mmol) and DIPEA (0.048 mL, 0.27 mmol) were stirred in DMF (1 mL) at room temperature for 4 hours. Additional morpholine (10.78 μL, 0.12 mmol) and DIPEA (0.024 mL, 0.14 mmol) were added and the resulting solution stirred at room temperature overnight. Water was added and the reaction mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography (6-50% EtOAc-hexanes) gave the title compound as a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].C(N(CC)CC)C.CCOCC.[F:23][C:24]([F:36])([F:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>C(OCC)(=O)C>[F:36][C:24]([F:23])([F:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([O:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])(=[O:32])=[O:33]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CCOP(=O)(CO)OCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOP(=O)(COS(=O)(=O)c1ccccc1C(F)(F)F)OCC
Reaction time: 8 h

Procedure:
A solution of 11.1 g of diethyl P-(hydroxymethyl)phosphonate (Example 17), 11 ml of triethylamine and 30 ml of ether was added dropwise over one hour to 15.5 g of 2-(trifluoromethyl)benzenesulfonyl chloride and 50 ml of anhydrous ether. The addition was mildly exothermic and a white precipitate began to form shortly after the addition was begun. The reaction was stirred overnight, then diluted with 300 ml of ethyl acetate and washed with three 85 ml portions of water. The organic phase was dried with magnesium sulfate, filtered and concentrated. The resulting crude product was purified via flash chromatography on Merck® silica gel (230-400 mesh) eluting with hexanes and ethyl acetate to yield 10.5 g of the desired product as an oil.
Reaction SMILES: C(NCC)C.CC(O)(C)C.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:14].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][C:26]=1[N+:34]([O-:36])=[O:35].OS(O)(=O)=O>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH2:32][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:14])=[CH:27][C:26]=1[N+:34]([O-:36])=[O:35]
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: c1ccccc1
Solvent: CCNCC
Product: O=C(CCC(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of zinc chloride (39.1 g, 287 mmol) in benzene (215 mL) was added diethylamine (22.24 mL, 215 mmol) and 2-methylpropan-2-ol (20.57 mL, 215 mmol). The resulting mixture was stirred at rt for 2 h, and 2-bromo-1-(4-nitrophenyl)ethanone (35.0 g, 143 mmol) and 1-(4-chloro-3-nitrophenyl)ethanone (42.9 g, 215 mmol) were added in one portion. The resulting mixture was stirred at rt overnight. Added 5% aq. H2SO4 (50 mL) and stirred vigorously to induce precipitation. The resulting solid was collected by filtration and washed successively with benzene, water, methanol, and CH2Cl2. The solid was dried in vacuo to give the title compound.
Reaction SMILES: [Mg].BrC(Br)C.[CH3:6][O:7][CH:8]([O:12][CH3:13])[CH2:9][CH2:10]Br.Cl[SiH2:15][CH:16]=[C:17]([CH3:19])[CH3:18]>O1CCCC1>[CH3:6][O:7][CH:8]([O:12][CH3:13])[CH2:9][CH2:10][SiH2:15][CH:16]=[C:17]([CH3:19])[CH3:18]
Reactant: CC(C)=C[SiH2]Cl
Reactant: COC(CCBr)OC
Agent: CC(Br)Br
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(CC[SiH2]C=C(C)C)OC
Temperature: 10 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirring magnesium granules (365 mg) in anhydrous tetrahydrofuran (15 mL), few drops of dibromoethane (˜50 μL) was added at room temperature under argon and the resultant mixture was stirred for 10 min. The reaction mixture was cooled to 10° C. and 3-bromopropionaldehyde dimethyl acetal (2.2 g) was introduced dropwise during 10 min. and allowed to stir at room temperature for 2 hours. After the completion of the Grignard formation, the reaction mixture was cooled to 0° C. and chlorodimethylvinylsilane (1.2 g) was added dropwise and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (20 mL) at 0° C. and the organics were extracted with t-butyl methyl ether (2×20 mL). The combined organic layers were dried and concentrated under reduced pressure to obtain the crude product. The pure product was obtained upon vacuum distillation of the crude material at 100° C. (2 mm Hg) in 80% yield (1.5 g).
Reaction SMILES: CN(C)C=O.CS(O[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:18]=[C:19]([CH3:34])[N:20]([CH2:24][C:25]3[S:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[C:21](=[O:23])[N:22]=2)[CH2:13][CH2:12]1)(=O)=O.[Br:35][C:36]1[CH:37]=[N:38][NH:39][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Br:35][C:36]1[CH:37]=[N:38][N:39]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[C:19]([CH3:34])[N:20]([CH2:24][C:25]4[S:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)[C:21](=[O:23])[N:22]=3)[CH2:13][CH2:12]2)[CH:40]=1
Reactant: Cc1nc(N2CCC(OS(C)(=O)=O)CC2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N2CCC(n3cc(Br)cn3)CC2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Yield: 48.5 %

Procedure:
To an N,N-dimethylformamide solution (1.0 mL) of 1-(6-methyl-4-oxo-5-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-4,5-dihydro-1,3,5-triazin-2-yl)piperidin-4-yl methanesulfonate (45.2 mg, 0.100 mmol) synthesized in Reference Synthesis Example 349, 4-bromo-1H-pyrazole (29.4 mg, 0.200 mmol) and potassium carbonate (27.6 mg, 0.200 mmol) were added and the resultant mixture was stirred at 100° C. for 1 hour. After the completion of the reaction, to the reaction solution, water was added and extraction with ethyl acetate from the reaction solution was performed. The organic layer was dried over anhydrous sodium sulfate and was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (24.4 mg, yield: 48%).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:7]=1[CH2:8][OH:9].C(O)(=O)C>O>[CH3:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:6]([NH:5][C:2]([NH2:3])=[O:1])[C:7]=1[CH2:8][OH:9]
Reactant: N#C[O-]
Reactant: Cc1cccc(N)c1CO
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(NC(N)=O)c1CO
Reaction time: 2.5 h
Yield: 73.9 %

Procedure:
A solution of potassium cyanate (1.62 g) in water (5 ml) was added dropwise to a mixture of 2-amino-6-methylbenzyl alcohol (1.37 g), water (5 ml), and acetic acid (6 ml) at room temperature. After being stirred for 2.5 hours, the resulting precipitates were collected by filtration, washed with water, and dried to give 2-methyl-6-ureidobenzyl alcohol (1.33 g).