Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.[Cl:31][C:32]1[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([Cl:50])[C:33]=1[O:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43]O)=[CH:39][CH:38]=1>ClCCl>[Br:1][CH2:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][CH2:35][O:34][C:33]2[C:32]([Cl:31])=[CH:48][C:47]([CH3:49])=[CH:46][C:45]=2[Cl:50])=[CH:38][CH:39]=1
Reactant: Cc1cc(Cl)c(OCCc2ccc(CO)cc2)c(Cl)c1
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cl)c(OCCc2ccc(CBr)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of triphenylphosphine dibromide (1.2 eq.) and Hunig's base (2 eq.) in dichloromethane (0.09 M) was added, dropwise over 5 min, {4-[2-(2,6-dichloro-4-methylphenoxy)ethyl]phenyl}methanol prepared in the previous step (1 eq.). The resulting mixture was stirred at RT for 2 h and then concentrated in vacuo. The residue was suspended in a 10:1 (v/v) Hex:ether solution and filtered through a pad of SiO2. The filtrate was concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=2[O:19][CH3:20])[CH:3]=1.CN.[C:23]([BH3-])#[N:24].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(OCC)(=O)C.C(O)(=O)C.CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:24][CH3:23])[C:12]=2[O:19][CH3:20])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: COc1c(C=O)cccc1Oc1cc(Cl)ccc1C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CNCc1cccc(Oc2cc(Cl)ccc2C#N)c1OC
Yield: 77.3 %

Procedure:
4-Chloro-2-(3-formyl-2-methoxy-phenoxy)-benzonitrile (0.52 g, 1.8 mmol), methylamine (2M in methanol, 2.7 ml, 5.4 mmol) and sodium cyanoborohydride (0.13 g, 2.1 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (70 ml) for 20 h. The solvent was removed in vacuo. The residue was treated with 10% aqueous sodium carbonate and extracted with ethyl acetate. Fumaric acid (0.21 g, 1.81 mmol) was added to the separated ethyl acetate layer and the solvent removed in vacuo. The residue was triturated with ethyl acetate overnight, filtered and dried to give 4-chloro-2-(2-methoxy-3-methylaminomethyl-phenoxy)-benzonitrile fumarate (583 mg, 717%) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[C:20]([C:28]4[CH:29]=[C:30]([NH:34]C(=O)C(F)(F)F)[CH:31]=[CH:32][CH:33]=4)=[N:21][N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=34)[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1.[Cl-].[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>>[NH2:34][C:30]1[CH:29]=[C:28]([C:20]2[C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)[CH:7]=4)[N:18]=3)=[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]3[N:21]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCCl)c3)n2)c1)C(F)(F)F
Reactant: C1COCCN1
Agent: [Cl-]
Product: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCN4CCOCC4)c3)n2)c1
Yield: 71 %

Procedure:
The compound was synthesized from N-(3-{3-[2-({3-[(3-chloropropyl)oxy]-phenyl}amino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)-2,2,2-trifluoroacetamide via chloride displacement with morpholine as described in Example 10, Step D to afford an orange solid in 71% yield. ES-LC/MS m/z 522 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([CH:5]([C:26]1[O:27][CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][CH:9]1[C:24](=[O:25])[N:11]2[C:12]([C:21]([OH:23])=[O:22])=[C:13]([CH2:16]OC(=O)C)[CH2:14][S:15][C@H:10]12)=[O:7])(=[O:4])=[O:3].[SH:31][C:32]1[S:33][C:34]([CH3:37])=[N:35][N:36]=1.C(=O)(O)[O-].[Na+].Cl>P([O-])([O-])([O-])=O.C(OCC)(=O)C.O>[CH3:1][S:2]([CH:5]([C:26]1[O:27][CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][CH:9]1[C:24](=[O:25])[N:11]2[C:12]([C:21]([OH:23])=[O:22])=[C:13]([CH2:16][S:31][C:32]3[S:33][C:34]([CH3:37])=[N:35][N:36]=3)[CH2:14][S:15][C@H:10]12)=[O:7])(=[O:3])=[O:4]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(c3ccco3)S(C)(=O)=O)[C@H]2SC1
Reactant: Cc1nnc(S)s1
Agent: Cl
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(c4ccco4)S(C)(=O)=O)[C@H]3SC2)s1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
7-[α-Methylsulfonyl(2-furyl)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (366.4 mg), 128 mg of 2-mercapto-5-methyl-1,3,4-thiadiazole and 68 mg of sodium bicarbonate were dissolved in a 0.1N phosphate buffer (pH 6.4), and the solution was stirred at 60° C. for 8 hours. Then, 20 ml of water, and 50 ml of ethyl acetate were added for extraction. The aqueous layer was acidified with 1H hydrochloric acid to a pH of 2, and extracted with ethyl acetate three times. The organic layer was washed four times with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure to obtain the product in powder form.
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[F:69][C:70]1([F:118])[C:82]2[CH:81]=[C:80]([C:83]3[NH:87][C:86]([C@@H:88]4[CH2:92][CH2:91][CH2:90][N:89]4[C:93](=[O:103])[C@@H:94]([NH:98][C:99](=[O:102])[O:100][CH3:101])[CH:95]([CH3:97])[CH3:96])=[N:85][CH:84]=3)[CH:79]=[CH:78][C:77]=2[C:76]2[C:71]1=[CH:72][C:73]([C:104]1[CH:105]=[CH:106][C:107]3[N:111]=[C:110]([C@@H:112]4[CH2:116][CH2:115][CH2:114][NH:113]4)[NH:109][C:108]=3[CH:117]=1)=[CH:74][CH:75]=2>>[CH3:60][O:59][C:57](=[O:58])[NH:56][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:113]1[CH2:114][CH2:115][CH2:116][C@H:112]1[C:110]1[NH:109][C:108]2[CH:117]=[C:104]([C:73]3[CH:74]=[CH:75][C:76]4[C:77]5[C:82](=[CH:81][C:80]([C:83]6[NH:87][C:86]([C@@H:88]7[CH2:92][CH2:91][CH2:90][N:89]7[C:93](=[O:103])[C@@H:94]([NH:98][C:99]([O:100][CH3:101])=[O:102])[CH:95]([CH3:96])[CH3:97])=[N:85][CH:84]=6)=[CH:79][CH:78]=5)[C:70]([F:69])([F:118])[C:71]=4[CH:72]=3)[CH:105]=[CH:106][C:107]=2[N:111]=1)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CCCN6)[nH]c5c4)ccc2-3)[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c5c4)ccc2-3)[nH]1)C(C)C

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-1-((S)-2-(5-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 872.50 [M+H]+. (97.5 mg, 59%).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[OH2:18]>CS(O)(=O)=O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:16]=[CH:17][C:3]([C:1]([NH2:2])=[O:18])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(Oc2ccc(C#N)cc2)cc1
Reactant: O
Agent: CS(=O)(=O)O
Product: COc1ccc(Oc2ccc(C(N)=O)cc2)cc1
Reaction time: 1 h

Procedure:
4-(4-Cyanophenoxy)-methoxybenzene (7.66 g, 34 mmol) and water (6.13 g, 340 mmol) in methanesulfonic acid (32.7 g) were heated to 80° C. for 16 hours. The cooled mixture was poured onto ice/water and after stirring for 1 hour the solid was collected and air dried yielding 8.4 g of 4-(4-methoxyphenoxy)benzamideas a white solid. GC-MS (m/z, EI): 243 [M]+.
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([NH:31][CH3:32])(=[O:30])=[O:29])[C:18]([Cl:33])=[CH:17][N:16]=2)=[CH:5][CH:6]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:10]1[CH2:11][CH:1]2[CH2:13][CH2:12][CH:8]([C:7]3[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[S:28]([NH:31][CH3:32])(=[O:30])=[O:29])[C:18]([Cl:33])=[CH:17][N:16]=2)=[CH:5][CH:6]=3)[CH2:9]1)(=[O:36])[CH3:35]
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Reactant: CC(=O)Cl
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(C)=O)C2)ncc1Cl

Procedure:
2-[2-(10-Acetyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide was prepared from 2-[2-(10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide and acetyl chloride in an analogous manner to Example 282. Product isolated as a yellow oil (25.3 mg, 77%). LCMS (m/e) 527 (M+1); 1H-NMR (CDCl3, 400 MHz,) major rotomer δ 9.09 (s, 1H), (d, 1H, J=9.5 Hz), 8.11 (s, 1H), 8.00-7.94 (m, 1H), 7.63-7.53 (s, 1H), 7.42-7.20 (m, 3H), 7.18-6.92 (m, 2H), 4.80-4.67 (m, 1H), 4.26-4.10 (m, 1H), 3.80-3.70 (m, 1H), 3.45-3.22 (m, 3H), 3.18-2.92 (m, 2H), 2.65 (d, 3H, J=2.3 Hz), 2.04 (s, 3H), 2.04-1.90 (m, 2H), 1.82-1.62 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH2:12][N:13]([CH3:18])[C:14](=[O:17])[CH:15]=[CH2:16].Br[C:20]1[CH:21]=[C:22]2[C:27](=[N:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]2.CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH2:12][N:13]([CH3:18])[C:14](=[O:17])/[CH:15]=[CH:16]/[C:20]1[CH:29]=[N:28][C:27]2[NH:26][C:25](=[O:30])[CH2:24][CH2:23][C:22]=2[CH:21]=1
Reactant: O=C1CCc2cc(Br)cnc2N1
Reactant: C=CC(=O)N(C)Cc1c(C)c2ccccc2n1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)n(C)c2ccccc12
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a stirred solution of N-(1,3-dimethyl-1H-indol-2-ylmethyl)-N-methylacrylamide (1.7 g, 7 mmole) in propionitrile (50 mL) was added 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (1.16 g, 5.1 mmole), DIEA (1.8 mL, 10.3 mmole), palladium(II) acetate (112 mg, 0.5 mmole), and tri-o-tolylphosphine (304 mg, 1.0 mmole). The reaction was purged with argon and heated at reflux for 16 hr, then was cooled to RT and concentrated under vacuum. Purification by flash chromatography on silica gel (5% methanol/CHCl3). trituration with ethyl acetate, filtration, and drying under vacuum gave the title compound (1.17 g, 59%) as an off-white solid: LCMS (ES) m/e 389.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:12]([OH:25])[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[C:5]2[CH3:32].[CH3:33][NH2:34]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:12]([OH:25])[CH2:13][NH:34][CH3:33])[CH:6]=[C:5]2[CH3:32]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC(O)C(c2ccccc2)n2cc(C)c3cc(F)ccc32)cc1
Solvent: CO
Product: CNC[C@@H](O)[C@H](c1ccccc1)n1cc(C)c2cc(F)ccc21
Reaction time: 12 h

Procedure:
A solution of (2S,3S)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol (1.03 g, 3.4 mmol) and p-toluenesulfonyl chloride (0.78 g, 4.1 mmol) in anhydrous pyridine (11 ml) was stirred at room temperature under nitrogen for 12 hours. The reaction was poured into a 1N aqueous solution of hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL). The organics were dried over anhydrous sodium sulfate, filtered, and concentrated to give (2S,3S)-toluene-4-sulfonic acid 3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester. The product was used in the next step without further purification. To a solution of toluene-4-sulfonic acid 3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester (1.6 g, 3.4 mmol) in methanol (10 mL) was added a 2N solution of methylamine in methanol (8.6 mL, 17 mmol) and the reaction stirred for 12 hours. Upon completion, the reaction was partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Biotage chromatography (FlasH40i, silica, 20% MeOH/dichloromethane) to give (1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol as a clear oil. The free base was dissolved in a minimum amount of ethanol and treated with a 2N ethereal solution of hydrochloric acid and stirred for 1 hour. The ethanol was removed in vacuo and the clear oil was triturated with ether/dichloromethane to give (1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol hydrochloride as a white solid. MS (ESI) m/z 313
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](Cl)=O)=[CH:3][CH:2]=1.[CH2:16]([N:18]([CH2:23][CH3:24])[C:19](=[O:22])[CH:20]=C)[CH3:17]>>[CH2:16]([N:18]([CH2:23][CH3:24])[C:19](=[O:22])[CH:20]=[CH:7][C:4]1[CH:5]=[CH:6][C:1]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:2][CH:3]=1)[CH3:17]
Reactant: C=CC(=O)N(CC)CC
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CCN(CC)C(=O)C=Cc1ccc(-c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 0.83 h

Procedure:
This compound is prepared from 10.83 g (50 millimols) of biphenyl-4-carboxylic acid chloride and 7.94 g (62.5 millimols) of N,N-diethylacrylamide, the mixture being stirred for 50 minutes at 120° C. The crude product is extracted, in a Soxhlet extractor, with 125 ml of n-hexane, and is recrystallised once from diethyl ether. 8.5 g (15% of theory) of pale yellow crystals, melting point 113.3° C., are obtained. Analysis for C10H21NO: calculated C 81.72%, H 7.53%, N 5.02%; found C 81.44%, H 7.50%, N 4.91%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>>[Cl-:14].[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cc1cccc2c1NC(=O)C2=O
Product: [Cl-]

Procedure:
By reacting 7-methylisatin with phosphorous pentachloride, there is obtained 7-methylisatin chloride which, on reaction with 5,6,7-trichloro 3(2H)-thianaphthenone, yields 5,6,7-trichloro-7'-methyl-2'-indole-2-thianaphthene indigo, which also is useful as a dyestuff.
Reaction SMILES: C1C([OH:7])=CC=CC=1C.[CH:9]1[C:14]([N:15]=[C:16]=O)=[CH:13][CH:12]=[C:11]([O:18]C2C=CC(N=C=O)=CC=2)[CH:10]=1.ClCl>>[CH3:9][C:10]1[N:15]([CH3:16])[CH:14]=[CH:13][C:12](=[O:7])[C:11]=1[OH:18]
Reactant: O=C=Nc1ccc(Oc2ccc(N=C=O)cc2)cc1
Reactant: Cc1cccc(O)c1
Agent: ClCl
Product: Cc1c(O)c(=O)ccn1C

Procedure:
Using the method described in Example 8, 240 g of m-cresol are mixed with 50.4 g of 4,4'-diisocyanatodiphenyl ether followed by 70.6 g of 4,4'-bis-α-chloroacetamidodiphenylether at 120°C and the mixture is then reacted at 185°C for 14 hours. 346 g of an approximately 30% polyhydantoin solution which has a chlorine content below 0.2% and a viscosity of 12460 cP20°C are obtained. Precipitation of this solution in methanol yields 210 g of a polyhydantoin with a nitrogen content of 10.4% and a chlorine content below 0.2%. The hydantoin structure is in both cases confirmed by the IR absorption bands at 1700 and 1755 cm-1.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH2:16][C@H:17]([OH:30])[CH2:18][O:19][C:20]1[C:28]2[NH:27][C:26](=[O:29])[NH:25][C:24]=2[CH:23]=[CH:22][CH:21]=1.[CH2:31]([N:38]([C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH3:64])[CH:56]=1)[S:39]([C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]2)=[CH:44][CH:43]=1)(=[O:41])=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(O)(=O)C>CN(C)C=O>[CH2:31]([N:38]([C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH3:64])[CH:56]=1)[S:39]([C:42]1[CH:43]=[CH:44][C:45]([N:48]2[CH2:49][CH2:50][CH:51]([NH:15][CH2:16][CH:17]([OH:30])[CH2:18][O:19][C:20]3[C:28]4[NH:27][C:26](=[O:29])[NH:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)[CH2:52][CH2:53]2)=[CH:46][CH:47]=1)(=[O:41])=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: COc1ccc(N(Cc2ccccc2)S(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(N(Cc2ccccc2)S(=O)(=O)c2ccc(N3CCC(NCC(O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)cc1OC
Reaction time: 8 h
Yield: 30.4 %

Procedure:
Sodium Triacetoxyborohydride (0.015 g, 0.72 mM) was added to a solution of 4-((2S)-3-Amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one(0.08 g, 0.36 mM), N-Benzyl-N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide(0.19 g, 0.39 mM), and acetic acid(0.025 ml, 0.43 mM) in anhydrous dimethylforamide(5 ml). The reaction was stirred overnight. The reaction was quenched with 50% H2O/sat. NaHCO3aq. (20 ml). The solids were captured on a filter and washed with ethyl acetate, diethyl ether, and hexanes to afford 0.075 g of the desired product as a brown solid. 1H NMR (DMSO) δ 1.31 (m, 2H), 1.89 (m, 2H), 2.71 (m, 2H), 2.87 (m, 3H), 3.53(s, 3H), 3.67 (s, 3H), 3.87 (m, 4H), 3.98 (m, 1H), 4.67(s, 2H), 4.95(bs, 1H), 6.44 (s, 1H), 6.59(m, 2H), 6.79 (m, 2H), 7.05 (d, 2H, J=8.7 Hz), 7.25 (m, 6H), 7.41(d, 2H, J=8.4 Hz), 10.59 (bs, 1H), 10.72 (bs, 1H); MS (ES) m/z: 688.1 (MH+); HRMS for C36H41N5O7S: 688.2799 (MH+)
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH2:9][CH2:10][OH:11])[C:7]([CH:12]=[CH:13][N:14]([CH3:16])[CH3:15])=[N:6][CH:5]=1)([O-:3])=[O:2].[C:17](Cl)(=[O:19])[CH3:18]>>[N+:1]([C:4]1[N:8]([CH2:9][CH2:10][O:11][C:17](=[O:19])[CH3:18])[C:7]([CH:12]=[CH:13][N:14]([CH3:15])[CH3:16])=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN(C)C=Cc1ncc([N+](=O)[O-])n1CCO
Reactant: CC(=O)Cl
Product: CC(=O)OCCn1c([N+](=O)[O-])cnc1C=CN(C)C

Procedure:
2,26 g. (0.01 mole) of 5-nitro-1-(2-hydroxyethyl)-2-(2-dimethylaminovinyl)-imidazole and 0.79 g. (0.01 mole) of acetyl chloride were reacted as described in Example 11. After pouring the reaction mixture on ice water, it was extracted with chloroform and the chloroform solution evaporated. The crude red oil exhibited the characteristic UV maxima in methanol:
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH3:11])=[CH:9][C:4]2=[CH:3][CH:2]=1.Cl.S1C2C=C[N:19]=CC=2C=C1CN>>[N:1]1[N:5]2[CH:6]=[CH:7][C:8]([CH:10]([NH2:19])[CH3:11])=[CH:9][C:4]2=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccn2nccc2c1
Reactant: NCc1cc2cnccc2s1
Agent: Cl
Product: CC(N)c1ccn2nccc2c1

Procedure:
Intermediate 3 was prepared from 1-(pyrazolo[1,5-a]pyridin-5-yl)ethanone (3-3) following the procedures similar to the procedures of intermediate D′ from D′-3. MS (m/z): 162 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:15][C@@:12]([CH2:16][OH:17])([CH2:13][O:14]2)[C@@H:11]([OH:18])[C@H:10]([OH:19])[C@H:9]3[OH:20])=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1.CO[CH:33](OC)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Na]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]23[O:15][C@@:12]4([CH2:16][O:17][CH:33]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[O:18][C@H:11]4[C@H:10]([OH:19])[C@H:9]2[OH:20])[CH2:13][O:14]3)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH3:30])=[CH:26][CH:27]=1
Reactant: COC(OC)c1ccccc1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(Cc2cc([C@@]34OC[C@]5(COC(c6ccccc6)O[C@H]5[C@H](O)[C@H]3O)O4)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol 28a (11.93 g, 27.3 mmol, purchased from Shanghai Caerulum Pharma Discovery Co., Ltd) in acetonitrile (40 mL) were added benzaldehyde dimethyl acetal (12.3 mL, 81.9 mmol) and p-toluenesulfonic acid monohydrate (4.7 g, 27.3 mmol) at room temperature. The mixture was stirred at room temperature for 30 min and adjusted with saturated aqueous sodium bicarnonate till pH becomes 7. The resulting mixture was extracted with ethyl actate (50 mL×2). The combined organic phases were washed with saturated aqueous sodium chloride (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=5/1 to give the title compound 28b as a white solid (14.3 g, 100%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH2:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][NH:10][CH2:9]1.C(N(CC)CC)C.O>ClCCl>[C:5]([N:10]1[CH2:9][CH2:8][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11]1)(=[O:7])[CH3:6]
Reactant: c1ccc2c(c1)CCNCC2
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2ccccc2CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
A solution of acetic anhydride (6.37 g, 0.062 mol) in dichloromethane (50 ml) was added dropwise to a stirred solution of 2,3,4,5-tetrahydro-1H-3-benzazepine (8.35 g, 0.057 mol) and triethylamine (8.7 ml) in dichloromethane (50 ml) at 0° C. under argon. After stirring at room temperature for 18 h, water (80 ml) was added and the organic layer separated. The organic layer was washed with 0.5 M hydrochloric acid (50 ml), saturated sodium bicarbonate solution (50 ml), water (50 ml) and then dried (Na2SO4). Evaporation of the solvent in vacuo gave the title compound (10.24 g, 95%) as a yellow oil which solidified on standing.
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](Cl)=O)[CH3:13]>O1CCOCC1.C(OCC)(=O)C>[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17]1[NH:1][C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[S:8](=[O:10])(=[O:9])[N:11]=1)[CH3:13]
Reactant: Nc1cccnc1S(N)(=O)=O
Reactant: CCOC(=O)CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CC1=NS(=O)(=O)c2ncccc2N1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 27.8 %

Procedure:
3-Amino-pyridine-2-sulfonic acid amide (1.8 g, 10 4 mmol) was dissolved in 1,4-dioxane (45 mL). Chlorocarbonyl-acetic acid ethyl ester (1.57 mL, 12.48 mmol) was added. The mixture was stirred at 90° C. for 1.5 h. Upon cooling, the mixture was diluted with ethyl acetate (300 mL) and washed with half-saturated aqueous sodium bicarbonate solution (100 mL) followed by saturated aqueous brine solution (100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oily residue was treated with toluene (36 mL) and triethylamine (9 mL). The mixture was stirred at 110° C. in a sealed tube for 1.5 h. The residue never completely dissolved. Upon cooling, the mixture was concentrated in vacuo to afford a thick oil. Trituration with a minimal amount of ethyl acetate (˜5 mL) solidified the product. The solids were collected by vacuum filtration and dried in vacuo for 16 h to afford the desired product, (1,1-dioxo-1,4-dihydro-1λ6-thia-2,4,8-triaza-naphthalen-3-yl)-acetic acid ethyl ester (0.3 g, 1.11 mmol, 11%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.21 (3H, t, J=7.0 Hz), 3.71 (2H, s), 4.16 (2H, quartet, J=7.1 Hz), 7.70-7.76 (2H, m), 8.62 (1H, dd, J1=4.0 Hz, J2=1.5 Hz), 12.29 (1H, bs). LC-MS (ESI) calcd for C10H11N3O4S 269.05, found 270.1 [M+H+].