Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:16])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10](Cl)[N:9]=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=1)[CH3:4].[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(#N)C>[NH2:1][C:2](=[O:16])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10]([N:21]2[CH2:22][CH2:23][CH:18]([OH:17])[CH2:19][CH2:20]2)[N:9]=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=1)[CH3:4]
Reactant: C[C@H](Nc1cc(C(N)=O)nc(Cl)n1)C(N)=O
Reactant: OC1CCNCC1
Solvent: CC#N
Product: C[C@H](Nc1cc(C(N)=O)nc(N2CCC(O)CC2)n1)C(N)=O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxamide (compound 37-6) (243 mg, 1 mmol), 4-hydroxylpiperidine (101 mg, 1 mmol), and TEA (0.17 mL, 1.2 mmol) was dissolved in acetonitrile (5 mL) and stirred at 70° C. for 1 hr, extracted with EtOAc (2×20 ml), and dried over MgSO4. The ethyl acetate was removed via rotary evaporator and the crude (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-hydroxypiperidin-1-yl)pyrimidine-4-carboxamide (compound 37-7) was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.CN(C)CCN(C)C.C([Li])CCC.CCCCCC.[I:35]I.S([O-])(O)=O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:3]=1[I:35]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ccn1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: O=S([O-])O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccc(Cl)c1I
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (4-chloropyridin-2-yl)carbamate (10 g, 43.7 mmol) and tetramethylethylenediamine (12 mL) in tetrahydrofuran (200 mL) at −70° C. was added 2.5M n-butyl lithium in hexane (52 mL, 131 mmol) over 30 minutes. The mixture was stirred at −70° C. for 1 hour and treated with a solution of iodine (27 g, 109 mmol) in 100 mL tetrahydrofuran at −70° C. The mixture was stirred at −70° C. for 30 minutes and warmed to room temperature. Saturated aqueous sodium hydrogen sulfite (200 mL) was added and the mixture stirred for 30 minutes. The mixture was extracted with ethyl acetate and the organic layers were washed with water and brine, dried over sodium sulfate, filtered, concentrated and precipitated from ethyl acetate/hexane to afford the title compound. LCMS: 298.9 (M+H—NCOOH)+.
Reaction SMILES: [CH:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:20])[O:18][CH3:19])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)=O.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].N1CCCCC1.C(O)(=O)C>O.C1(C)C=CC=CC=1>[CH3:19][O:18][C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][O:7][C:6]2[CH:21]=[CH:22][C:3]([CH:1]=[C:27]3[S:23][C:24](=[O:29])[NH:25][C:26]3=[O:28])=[CH:4][CH:5]=2)=[CH:11][CH:12]=1)=[O:20]
Reactant: O=C1CSC(=O)N1
Reactant: COC(=O)Nc1ccc(CCOc2ccc(C=O)cc2)cc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)Nc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Yield: 71.2 %

Procedure:
2 g (6.7 mmole) methyl N-{4-[2-(4-formylphenoxy)ethyl]phenyl}carbamate, 1.57 g (13.4 mmole) 2,4-thiazolidinedione, piperidine, acetic acid and toluene were refluxed with water separation in a Dean-Stark apparatus for 3 hours. The formed yellow precipitate was collected by filtration giving 1.9 g (yield 71.2%) of 5-(4-[2-(4-methoxycarbonylaminophenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: Cl.[CH2:2]1[CH:6]2[CH2:7][NH:8][CH2:9][CH:5]2[CH2:4][N:3]1[C:10]([NH2:12])=[O:11].[CH2:13]1C2CNCC2CN1C(N)=O.C([O-])([O-])=O.[K+].[K+].CS([CH2:34][CH2:35][C:36]1[CH:52]=[CH:51][C:39]([O:40][C:41]2[S:42][C:43]3[CH:49]=[C:48](C)[CH:47]=[CH:46][C:44]=3[N:45]=2)=[CH:38][CH:37]=1)(=O)=O>C(Cl)Cl.CO.C(O)(CC)(C)C>[CH3:13][C:46]1[C:44]2[N:45]=[C:41]([O:40][C:39]3[CH:38]=[CH:37][C:36]([CH2:35][CH2:34][N:8]4[CH2:7][CH:6]5[CH2:2][N:3]([C:10]([NH2:12])=[O:11])[CH2:4][CH:5]5[CH2:9]4)=[CH:52][CH:51]=3)[S:42][C:43]=2[CH:49]=[CH:48][CH:47]=1
Reactant: Cc1ccc2nc(Oc3ccc(CCS(C)(=O)=O)cc3)sc2c1
Reactant: NC(=O)N1CC2CNCC2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc2sc(Oc3ccc(CCN4CC5CN(C(N)=O)CC5C4)cc3)nc12
Temperature: 80 °C
Yield: 5 %

Procedure:
A solution of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid amide hydrochloride in 50% CH2Cl2/CH3OH was treated with DOWEX Monosphere 550A (OH) anion-exchange resin to afford the free base. The DOWEX resin was filtered and the resulting solution was concentrated and used without further purification. To a solution of this hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid amide (85 mg, 0.54 mmol) and K2CO3 (116 mg, 0.84 mmol) in tert-amyl alcohol (2.6 mL) was added 2-[4-(2-methanesulfonyl-ethyl)-phenoxy]-6-methyl-benzothiazole (120 mg, 0.34 mmol). The reaction mixture was heated to 80° C. for 16 h. The reaction mixture was filtered and washed with CH3OH. The resulting liquid was purified by preparative reverse phase HPLC to afford the title compound (11 mg, 5%). MS (ESI): mass calcd. for C23H26N4O2S, 422.55; m/z found, 423.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.62 (d, J=8.3 Hz, 1H), 7.48 (s, 1H), 7.28 (s, 4H), 7.20 (dd, J=8.3, 1.1 Hz, 1H), 4.39 (s, 2H), 3.60 (dd, J=10.2, 8.2 Hz, 2H), 3.30 (dd, J=10.0, 1.9 Hz, 2H), 2.98-2.87 (m, 2H), 2.86-2.80 (m, 2H), 2.76 (dd, J=9.3, 6.9 Hz, 2H), 2.74-2.67 (m, 2H), 2.53 (dd, J=9.3, 3.4 Hz, 2H), 2.45 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)=[N:6][C:5]=1[NH2:23])(=[O:3])[CH3:2].[ClH:24]>O1CCOCC1>[ClH:24].[ClH:24].[NH2:23][C:5]1[N:6]=[C:7]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)[S:8][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)c1sc(NC2CCCN(C(=O)OC(C)(C)C)C2)nc1N
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1sc(NC2CCCNC2)nc1N

Procedure:
Analogously to the preparation of Example 38A, 160 mg (0.15 mmol) of tert-butyl 3-[(5-acetyl-4-amino-1,3-thiazol-2-yl)amino]piperidine-1-carboxylate (Example 49A) and 20 ml of hydrochloric acid in dioxane (4M) gave 40 mg (87% of theory) of the product as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([S:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12])[CH3:10].C(N(C(C)C)CC)(C)C.O>CC(N(C)C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:16][CH2:15][N:14]([S:11]([CH2:9][CH3:10])(=[O:12])=[O:13])[CH2:19][CH2:18]2)=[N:3][CH:4]=1
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: Brc1ccc(Br)nc1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CCN(c2ccc(Br)cn2)CC1

Procedure:
2,5-Dibromopyridine (1 g) was heated in dimethylacetamide (2.5 ml) with ethanesulfonylpiperazine (0.752 g) and diisopropylethylamine (1.84 ml) at 120° C. for 18 h. After cooling, the reaction mixture was poured into water (30 ml) and the precipitated solid was collected by filtration. The product was purified by column chromatography eluting with dichloromethane (0.50 g).
Reaction SMILES: [CH:1]1([N:6]([CH3:33])[C:7]2[C:8]([CH3:32])=[C:9]([CH:23]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:25]=2)[C:10]([NH:12][CH2:13][C:14]2[C:15](=[O:22])[NH:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:36]([BH3-])#N.[Na+]>CO>[CH:1]1([N:6]([CH3:33])[C:7]2[C:8]([CH3:32])=[C:9]([CH:23]=[C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH3:36])[CH2:28][CH2:27]3)[CH:25]=2)[C:10]([NH:12][CH2:13][C:14]2[C:15](=[O:22])[NH:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(N3CCNCC3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCN(C)CC3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
3-(Cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(piperazin-1-yl)benzamide (free base) (0.100 g, 0.223 mmol) was dissolved in methanol (5 mL) and cooled to 0° C. before formalin (0.033 g, 1.1 mL, 2.23 mmol) was added. The resulting reaction mixture was stirred at same temperature for 30 minutes. Sodium cyanoborohydride (0.013 g, 0.22 mmol) was added to above reaction mixture and stirred at room temperature for 4 h. After completion, solvent was removed under reduced pressure and water added to the residue, with extraction carried out using DCM. The combined organic layers were dried, concentrated and purified by column chromatography to provide desired 3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(4-methylpiperazin-1-yl)benzamide (0.037 g, 36%).
Reaction SMILES: [CH:1]([S:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)([CH3:3])[CH3:2].[Br:10]N1C(=O)CCC1=O.C(OCC)(=O)C.CCCCCC>CN(C=O)C>[Br:10][C:7]1[S:6][C:5]([S:4][CH:1]([CH3:3])[CH3:2])=[N:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)Sc1nccs1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Sc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
To a solution of 2-(isopropylthio)thiazole (260 mg, 1.63 mmol) in DMF (2 mL) was added N-bromosuccinimide (435.8 mg, 2.45 mmol). The mixture was stirred at room temperature for 3 hours then subjected to flash column chromatography using 10% ethyl acetate/hexane to give a yellow oil (390 mg, 100% yield). LCMS (Conditions C): Tr 3.67 min.; (M+H): 237.86 (30%), 239.86 (30%), 195.86 (100%), 197.86 (100%).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].[OH-].[NH4+:23].C1(C)C(S(Cl)(=O)=O)=CC=CC=1>C(Cl)(Cl)Cl.ClCCl>[NH2:23][C:8]1[C:7]2[N:16]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[C:6]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCO
Reactant: [NH4+]
Agent: Cc1ccccc1S(=O)(=O)Cl
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCO

Procedure:
4-(2-Propyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (7.27 g, 25.7 mmol, which can be prepared using the method described in Example 43 Part A) was oxidized and then animated using a modification of the general method described in Example 4 Part H. The oxidation was run in chloroform in lieu of dichloromethane and the crude N-oxide was isolated prior to being dissolved in dichloromethane and treated with ammonium hydroxide and toluene sulfonyl chloride. 3.82 g of 4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1.[N:31]1([C:38]2[S:39][C:40]3[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=3[N:42]=2)[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27][N:34]3[CH2:35][CH2:36][CH2:37][N:31]([C:38]4[S:39][C:40]5[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=5[N:42]=4)[CH2:32][CH2:33]3)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1
Reactant: c1ccc2sc(N3CCCNCC3)nc2c1
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1
Product: COc1ccc(CNC(=O)C2(CCCCN3CCCN(c4nc5ccccc5s4)CC3)c3ccccc3-c3ccccc32)cc1

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-methoxy-benzylamide and 2-[1.4]diazepan-1-yl-benzothiazole.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13]1>>[NH2:1][C:2]1[CH:9]=[C:8]([O:17][C@@H:14]2[CH2:15][CH2:16][N:12]([CH3:11])[CH2:13]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: CN1CC[C@@H](O)C1
Reactant: N#Cc1cnc(N)cc1F
Product: CN1CC[C@@H](Oc2cc(N)ncc2C#N)C1

Procedure:
From intermediate 21 and (R)-1-methylpyrrolidin-3-ol, reacted in an analogous manner to the preparation of intermediate 47. (UPLC-MS 3) tR 0.28 min; ESI-MS 219.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:17]2[CH2:22][CH2:21][CH:20]([C:23]([F:26])([F:25])[F:24])[CH2:19][CH2:18]2)=[C:8]([CH:16]=1)[C:9]([NH:11][CH2:12][CH:13]1[CH2:15][CH2:14]1)=[O:10])([O-])=O.CSC1C2C(=CC(Br)=CC=2Br)NC=1SC>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]([F:26])([F:24])[F:25])[CH2:21][CH2:22]2)=[C:8]([CH:16]=1)[C:9]([NH:11][CH2:12][CH:13]1[CH2:14][CH2:15]1)=[O:10]
Reactant: O=C(NCC1CC1)c1cc([N+](=O)[O-])ccc1N1CCC(C(F)(F)F)CC1
Agent: [Pd]
Agent: CSc1[nH]c2cc(Br)cc(Br)c2c1SC
Solvent: C1CCOC1
Product: Nc1ccc(N2CCC(C(F)(F)F)CC2)c(C(=O)NCC2CC2)c1

Procedure:
Prepared analogously to example 42c with 5-nitro-2-(4-trifluoromethyl-piperidin-yl)-N-cyclopropylmethylbenzamide (370 mg; 1 mmol) and Pd/C 10%/H2 (60 mg/3 bar) in 60 mL THF. Yield: quantitative; MS: [M+H]+=342; HPLC: Rt=1.68 min (Method MC-6)
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:20][C:21]([Cl:27])=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[NH:6][C:7](=[O:19])[CH2:8][S:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Cl:27][C:21]1[CH:20]=[C:5]2[C:4]([C:3]([OH:2])=[C:8]([S:9][CH2:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:19])[NH:6]2)=[C:23]([N+:24]([O-:26])=[O:25])[CH:22]=1
Reactant: COC(=O)c1c(NC(=O)CSCCCc2ccccc2)cc(Cl)cc1[N+](=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)cc([N+](=O)[O-])c2c(O)c1SCCCc1ccccc1
Reaction time: 1 h
Yield: 73.6 %

Procedure:
0.55 g (1.3 mmol) of 4-chloro-6-nitro-N-(3-phenylpropylthio)acetyl-anthranilic acid methyl ester are placed in 6 ml of tetrahydrofuran at 0° under nitrogen. 2.6 ml of a 1-molar tetrahydrofuran solution of sodium bis-trimethylsilylamide are added dropwise thereto. The mixture is then stirred for 1 hour at 0°. The reaction mixture is poured into 50 ml of 2N hydrochloric acid/ice and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated by evaporation. The residue is taken up in a small amount of ethyl acetate, and hexane is added until precipitation begins. The precipitate formed is filtered off with suction and dried. 374 mg (73% of theory) of 7-chloro-5-nitro-4-hydroxy-3-(3-phenylpropylthio)-2(1H)-quinolone are obtained in the form of red crystals having a melting point of 177°-184°.
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[N+:23]([O-:25])=[O:24])[CH:9]=[CH:8][C:7]=1[N+:26]([O-:28])=[O:27])(=[O:5])[OH:4])[CH3:2].[CH3:29][O:30][C:31](=[O:34])[CH2:32]Br>>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[N+:23]([O-:25])=[O:24])[CH:9]=[CH:8][C:7]=1[N+:26]([O-:28])=[O:27])(=[O:4])[O:5][CH2:32][C:31]([O:30][CH3:29])=[O:34])[CH3:2]
Reactant: CCP(=O)(O)c1cc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])ccc1[N+](=O)[O-]
Reactant: COC(=O)CBr
Product: CCP(=O)(OCC(=O)OC)c1cc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 32, P-ethyl-2-nitro-5-(2-nitro-4-trifluoromethyl-anilino)phenylphosphinic acid is reacted with methylbromoacetate to give methoxycarbonylmethyl P-ethyl-2-nitro-5-(2-nitro-4-trifluoromethylanilino)phenylphosphinate.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7](=[O:9])[CH3:8])[S:5][CH:6]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:17][CH2:1][C:2]1[N:3]=[C:4]([C:7](=[O:9])[CH3:8])[S:5][CH:6]=1
Reactant: CC(=O)c1nc(C)cs1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1nc(CBr)cs1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A solution of 2a (4.38 g, 0.031 mol), NBS (5.8 g, 0.033 mol) and 100 mg of AIBN in 40 mL of carbon tetrachloride was heated at 70° C. for 16 h. Cooled to rt and the precipitate was filtered. The solvent was concentrated in vacuo to an oil that was subjected to flash chromatography (5% ethyl acetate/95% hexanes) to give 4.95 g (72%) of the desired product 3a. 1H NMR (CDCl3) δ 7.8 (s, 1H), 4.8 (s, 2H), 2.8 (s, 3H).
Reaction SMILES: [OH-:1].[Na+].Cl[O-].[Na+].[CH3:6][C:7]1([CH3:22])[CH2:16][C:15]([CH3:18])([CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:19](=[O:21])C)[CH:13]=2)[O:8]1>O.O1CCOCC1>[CH3:22][C:7]1([CH3:6])[CH2:16][C:15]([CH3:17])([CH3:18])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:19]([OH:21])=[O:1])[CH:13]=2)[O:8]1
Reactant: [OH-]
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)CC(C)(C)c2cc(C(=O)O)ccc2O1
Temperature: 65 °C

Procedure:
A solution of 2.0 (50 mmol) of NaOH in 10 ml of water was treated with 50 ml of 10% aqueous sodium hypochlorite solution and then with a solution of 1.04 g (4.31 mmol) of 2,2,4,4-tetramethyl-6-acetylchroman (Compound 46) in 15 ml of dioxane. The mixture was heated at 65° C. for 40 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and then diluted with water. The mixture was then washed with ether and the aqueous layer was treated with sodium metabisulphite until it was negative to the potassium iodide - starch test. The aqueous layer was then acidified with 10% H2SO4 and then extracted with ether. This ether extract was washed with water and saturated NaCl solution and then dried (MgSO4). Solvent was removed in-vacuo and the residue recrystallized from ethyl acetate to give the title compound as a white solid. PMR (CDCl3): & 1.39 (6H, s), 1.40 (6H, s), 1.88 (2H, s), 6.85 (1H, d, J~8.7 Hz), 7.85 (1H, dd, J~8.7 Hz, 2.1 Hz), 8.09 (1H, d, J~2.1 Hz). MS exact mass, m/e 234.1256 (calcd. for C14H18O3, 234.1256).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[Li].N.[Cl-].[NH4+]>O1CCCC1.O.C(O)C>[CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]1[OH:21]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)C1
Yield: 64.2 %

Procedure:
Add dl-3-methoxyestra-1,3,5(10)-trien-17β-ol (1.3 g) in tetrahydrofuran (40 ml) to a stirred solution of lithium (1.3 g) in liquid ammonia (100 ml). After 15 minutes add ethanol (20 ml) dropwise and when the blue color is discharged add ammonium chloride and water and extract the mixture with ether. Wash, dry and evaporate the ethereal solution and recrystallize the residue from ethanol-hexane to obtain dl-3-methoxyestra-2,5(10)-dien-17β-ol (0.84 g), m.p. 120°-123°; infrared absorption maxima at 3.25 μ, 5.8 μ, 6 μ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([O:16][CH3:17])=[O:15].[C:18]1([CH2:24][CH2:25][CH2:26]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:26][CH2:25][CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: BrCCCc1ccccc1
Reactant: COC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Product: COC(=O)Cc1c(C)n(CCCc2ccccc2)c2ccc(OC)cc12

Procedure:
Prepare by a method similar to Example 48 using methyl [5-methoxy-2-methyl-indol-3-yl]-acetate and 3-phenylpropyl bromide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[S:11].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:10](=[S:11])[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1cnc(Cl)cc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: S=c1[nH]c2cnc(Cl)cc2[nH]1
Reaction time: 8 h

Procedure:
A stirred mixture of 6-chloropyridine-3,4-diamine (500 mg, 3.48 mmol), 1,1′-thiocarbonyldiimidazole (1.24 g, 6.97 mmol), and triethylamine (0.49 mL, 3.48 mmol) in anhydrous DMF (15.0 mL) was microwaved in a Biotage Initiator at 100° C. at normal power for 1 h. Then the reaction mixture was evaporated at reduced pressure, and the resulting residue extracted with DCM (200 mL) and allowed to stand at 10° C. overnight. The mixture filtered and the solids washed with cold DCM (2×20 mL), and air dried to afford the title compound as a solid. LC-MS: calculated for C6H4ClN3S 184.98 observed m/e: 186.07 (M+H)+ (Rt 0.62/2.0 min)
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>C(O)(C)C>[Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[CH:7]=[C:6](/[CH:11]=[CH:14]/[N:15]([CH3:17])[CH3:16])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(Cl)nc(Cl)c1C#N
Reactant: COC(OC)N(C)C
Solvent: CC(C)O
Product: CN(C)/C=C/c1cc(Cl)nc(Cl)c1C#N
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To 2,6-dichloro-4-methylnicotinonitrile (20.3 g, 0.108 mol) in 200 mL of isopropyl alcohol is added N,N-dimethylformamide dimethylacetal (14.4 mL, 0.108 mol) and the reaction is stirred at 65° C. for 18 hrs. After the reaction is cooled to ambient temperature, the precipitate is collected by filtration, washed with 50 mL of isopropyl alcohol, and air dried giving (E)-2,6-Dichloro-4-(2-(dimethylamino)vinyl)nicotinonitrile as a yellow solid. MS (ES+) calcd. 242.02. found 242.10 (MH+). H-NMR (600 MHz, DMSO-d6) 2.90 (br.s, 3H), 3.17 (br.s, 3H), 5.05 (d, J=12.6 Hz, 1H), 7.61 (s, 1H), 8.09 (d, J=12.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][CH2:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1)=O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][CH2:3][C:4]1[N:12]2[C:8]([S:9][CH:10]=[CH:11]2)=[CH:7][N:6]=1
Reactant: COCC(=O)NCc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: COCc1ncc2sccn12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.1 %

Procedure:
To 570 mg (3.1 mmol) of the above-obtained 2-(methoxyacetylamino)methylthiazole was added 5 ml of phosphorus oxychloride. The mixture was refluxed for 4 hours, cooled to room temperature, and concentrated to dryness under reduced pressure. To the residue were added 2 ml of water and 5 ml of methylene chloride to obtain a solution, to which was added 2 g of potassium carbonate little by little. The mixture was stirred for 5 minutes. The organic layer was separated, and the aqueous layer was extracted two times with methylene chloride. The combined organic layers were dried over anhydrous potassium carbonate, concentrated under reduced pressure, and purified by flash column chromatography using silica gel, eluting with ethyl acetate. A fraction containing the desired compound was concentrated to dryness. The residue was further purified by column chromatography using Sephadex LH 20, eluting with a 1:1 mixture of chloroform and methanol to give 110 mg (yield 21%) of the title compound.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[CH3:32][O:33][C:34](=[O:40])[C:35]([CH3:39])([CH3:38])[CH2:36][NH2:37]>CO>[CH3:32][O:33][C:34](=[O:40])[C:35]([CH3:39])([CH3:38])[CH2:36][NH:37][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)C(C)(C)CN
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Solvent: CO
Product: COC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 150 °C
Yield: 97.2 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (52 mg, 0.127 mmol) and 3-amino-2,2-dimethyl-propionic acid methyl ester (83 mg, 0.633 mmol) in MeOH (3 mL) was heated to 150° C. for 1 h in a CEM microwave reactor. The solvent was evaporated in vacuo and the residue was chromatographed (0-40% EtOAc/hexanes) to give 63 mg of the title compound as a yellow oil. MS: (+) m/z 511.22 (M+1).