Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]#[N:14])[CH:10]=2)[NH:5]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:27][CH2:26][C@H:25]3[CH2:28][N:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@@H:24]23)=[CH:18][N+:17]=1[O-:36]>>[C:13]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4]([OH:3])=[C:12]2[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:27][CH2:26][C@H:25]3[CH2:28][N:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@@H:24]23)=[CH:18][N+:17]=1[O-:36])#[N:14]
Reactant: CCOC(=O)N1C[C@@H]2CCN(Cc3ccc(Cl)[n+]([O-])c3)[C@@H]2C1
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)N1C[C@@H]2CCN(Cc3ccc(-c4c(O)[nH]c5ccc(C#N)cc45)[n+]([O-])c3)[C@@H]2C1

Procedure:
The titled compound was prepared in analogy to example 4.1 using sodium hydride on mineral oil (101 mg, 2.53 mmol), 2-oxoindoline-5-carbonitrile (300 mg, 1.897 mmol), and 2-chloro-5-(((3aS,6aS)-5-(ethoxycarbonyl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)methyl)pyridine 1-oxide (412, 1.265 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](Br)[C:6]([CH:10]2[CH2:12][CH2:11]2)=[C:5]([F:13])[C:3]=1[NH2:4].[CH3:14]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:14])[C:6]([CH:10]2[CH2:12][CH2:11]2)=[C:5]([F:13])[C:3]=1[NH2:4]
Reactant: CB1OB(C)OB(C)O1
Reactant: Nc1c(Cl)cc(Br)c(C2CC2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(Cl)c(N)c(F)c1C1CC1
Temperature: 25 °C

Procedure:
2-Chloro-4-bromo-5-cyclopropyl-6-fluoroaniline (14.0 g, 53 mmol), trimethylboroxine (13.4 g of 50% solution in THF, 53 mmol), tetrakis(triphenylphosphine)palladium(0) (2.5 g, 2.2 mmol) and potassium carbonate (14.0 g, 101 mmol) are combined and stirred in 250 mL of a 4:1 DME/water solution. The mixture is degassed by repeated alternating application of vacuum and positive nitrogen pressure (10×). The mixture is heated to reflux temperature for 2 days and then cooled to room temperature. Most of the DME is removed by rotary evaporator and the residual mixture is partitioned between Et2O (500 mL) and water (500 mL). The organic phase is washed with brine (3×250 mL), dried (MgSO4) and concentrated by rotary evaporator. The crude product is purified using flash chromatography (5% CH2Cl2/hexanes) to give 2-chloro-4-methyl-5-cyclopropyl-6-fluoroaniline a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[CH3:11]OC(=O)OC.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([CH3:11])[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: COC(=O)OC
Reactant: N#CCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C#N)c1ccc(Br)cc1
Temperature: 180 °C
Reaction time: 16 h

Procedure:
An autoclave is charged with 25.0 g (128 mmol) 4-bromobenzylcyanide, 190 mL dimethylcarbonate and 0.900 g (6.51 mmol) K2CO3 and stirred for 16 h at 180° C. Then the reaction mixture is allowed to cool to r.t., the mixture is diluted with EtOAc and washed with water (1×), aq. 10% Na2S2O3 solution (1×) and brine (1×). The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The residue is purified by destillation (bath temperature 204° C., head temperature 153° C.).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].F[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([I:21])[CH:13]=1>CS(C)=O.C(OCC)(=O)C>[I:21][C:14]1[CH:13]=[C:12]([N:8]2[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]2)[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCN(c2cc(I)cc([N+](=O)[O-])c2)CC1
Temperature: 130 °C

Procedure:
1-(methylsulfonyl)piperazine (627 mg, 3.82 mmol) was added to a solution of 1-fluoro-3-iodo-5-nitrobenzene (510 mg, 1.91 mmol) in dimethylsulfoxide (2 mL). The reaction was heated to 130° C. for 60 minutes in the microwave reaction, then allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with 1:1 water:brine (3×30 mL). The organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) provided 1-(3-iodo-5-nitrophenyl)-4-(methylsulfonyl)piperazine as a bright yellow foam. 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.70 (s, 1H), 7.51 (s, 1H), 3.42 (s, 8H), 2.87 (s, 3H).
Reaction SMILES: [Cl-].[Eu+3].[Cl-].[Cl-].[Na+].[NH2:6][C@H:7]([C:27]([O-:29])=[O:28])[CH2:8][C:9]1[CH:16]=[C:14]([I:15])[C:13]([O:17][C:18]2[CH:25]=[C:23]([I:24])[C:22]([OH:26])=[C:20]([I:21])[CH:19]=2)=[C:11]([I:12])[CH:10]=1>CN(C)C=O.C(O)C>[NH2:6][C@H:7]([C:27]([OH:29])=[O:28])[CH2:8][C:9]1[CH:10]=[C:11]([I:12])[C:13]([O:17][C:18]2[CH:19]=[C:20]([I:21])[C:22]([OH:26])=[C:23]([I:24])[CH:25]=2)=[C:14]([I:15])[CH:16]=1
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)[O-]
Agent: [Cl-]
Agent: [Eu+3]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O

Procedure:
Fluorescent compound (v) synthesized in Example 4 was dissolved in dimethylformamide at a concentration of 5.0×10-5M, and thyroxine sodium salt was dissolved in ethanol at a concentration of 5.0×10-5M. The fluorescent compound (v) solution (100 μl) and the thyroxine sodium salt solution (100 μl) of ethanol were mixed and incubated for 30 minutes at room temperature with stirring. The resulting solution was subjected to a HPLC purification (column: AP-313, YMC Co., solvent: methanol: water=3:7(v:v) including 0.02% acetic acid) and the fluorescent compound (v)-labelled thyroxine was purified. The fluorescent compound (v)-labelled thyroxine was identified by measuring the thyroxine activity using an enzyme immunoassay (Boehringer Mannheim GmbH), and by measuring fluorescence intensity of the solution prepared by mixing equal volume of europium chloride (1×10-5M) and the fraction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[C:12](=[CH:17][N:18]([CH3:20])[CH3:19])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Reaction time: 6 h

Procedure:
A mixture of 1-tert-butoxycarbonyl piperidine-4-one and N,N-dimethylformamide dimethylacetal was stirred for 6 hours heated to reflux to give 1-tert-butoxycarbonyl-3-[(dimethylamino)methylene]piperidine-4-one. A mixture of the obtained 1-tert-butoxycarbonyl-3-[(dimethylamino)methylene]piperidine-4-one, 2-hydrazinoethanol and MeOH was stirred for two hours heated to reflux to give a mixture of 2-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-2-yl)ethanol and 2-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1-yl)ethanol. A mixture of the obtained mixture, 4M HCl-EtOAc solution and EtOH was stirred for two hours at room temperature to give a mixture of 2-(4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-2-yl)ethanol dihydrochloride and 2-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1-yl)ethanol dihydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.[C:12](Cl)(Cl)=[O:13]>C(O)(=O)C.ClC1C=CC=CC=1>[NH:1]1[C:2]2=[C:11]3[C:6](=[CH:5][CH:4]=[CH:3]2)[CH2:7][CH2:8][CH2:9][N:10]3[C:12]1=[O:13]
Reactant: Nc1cccc2c1NCCC2
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1
Solvent: CC(=O)O
Product: O=c1[nH]c2cccc3c2n1CCC3
Yield: 88 %

Procedure:
To a solution of 10.77 g of 8-amino- 1,2,3,4-tetrahydroquinoline in glacial acetic acid (30 ml) was added dropwise a 21.75% solution of phosgene in chlorobenzene (30 ml), under nitrogen, with stirring. After the addition was complete, the mixture was heated under reflux, with stirring for one hr and evaporated. The residue was taken up in 10% ammonium hydroxide solution (75 ml) and extracted with dichloromethane. The organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. Ether was added to the residue and the mixture was chilled. The precipitate was collected to give 11.2 g (88%) of product.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.Cl.CN(C)CCCN=C=NCC.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[N:27]1[C:35]2[C:30](=[CH:31][C:32]([C:36]3[N:40]=[CH:39][N:38]([C:41]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:37]=3)=[CH:33][CH:34]=2)[C:29]([C:60]2[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=2)=[N:28]1>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:66][C:62]2[CH:63]=[CH:64][CH:65]=[C:60]([C:29]3[C:30]4[C:35](=[CH:34][CH:33]=[C:32]([C:36]5[N:40]=[CH:39][N:38]([C:41]([C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=6)([C:48]6[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=6)[C:54]6[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=6)[N:37]=5)[CH:31]=4)[N:27]([CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26][O:21]4)[N:28]=3)[CH:61]=2)=[O:8])=[CH:2]1
Reactant: O=C(O)c1ccoc1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccoc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of furan-3-carboxylic acid (0.056 g, 0.496 mmol) in 2.5 mL of dichloromethane, was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) as a solid (0.105 g, 0.546 mmol). The solution was stirred at room temperature for 10 min before 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) dissolved in 1 mL of dichloromethane, was added. The reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between dichloromethane and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 697 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:3]=1[NH2:4].O.[C:15]1(C)[CH:20]=[CH:19][C:18](S(O)(=O)=O)=[CH:17][CH:16]=1.C(CC(=O)C)C(C)=O.O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:3]=1[N:4]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:20]1[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: CC(=O)CCC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(C)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 811.4 %

Procedure:
To a refluxing solution of 9.20 g (40.0 mmoles) of 2,6-dichloro-4-trifluoromethylaniline and 0.76 g (4.0 mmoles) of p-toluenesulfonic acid monohydrate in 25 mL of benzene was added dropwise over an 8 hour period with a syringe pump 9.40 mL (9.14 g, 80.1 mmoles) of acetonylacetone. Throughout the addition, water was removed via a Dean-Stark trap. The reaction mixture was then cooled and partitioned with a saturated aqueous solution of NaHCO3 which was back-extracted with ether. The combined organic layers were dried over anhydrous Na2SO4 concentrated. The residual brown oil was chromatographed on silica gel with a 95:5 v/v hexane-EtOAc eluent to afford 10.0 g (81%) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-2,5-dimethylpyrrole as a light brown solid of melting point 63° C.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[CH:4][C:3]1=[O:8].[Br:9]Br.C(N(CC)CC)C>CO>[CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([Br:9])[C:3]1=[O:8]
Reactant: CN1C(=O)C=CC1=O
Reactant: BrBr
Solvent: CO
Solvent: CCN(CC)CC
Product: CN1C(=O)C=C(Br)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
To N-methyl maleimide (0.5 g, 4.5 mmol) in methanol (22.5 mL) was added bromine (0.52 mL, 10 mmol) dropwise. The reaction mixture was stirred at room temperature for 24 hours. Solvent was removed in vacuo and the reaction mass was dissolved in tetrahydrofuran (20 mL) and triethylamine (0.8 mL, 5.85 mmol) added, then stirred for 24 hours at room temperature. The material was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate, 7:3) to afford a pale white powder (0.761 g, 4.0 mmol) in 89% yield.
Reaction SMILES: O[C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.P(Cl)(Cl)(Cl)=O.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>>[CH2:21]([N:23]([CH2:24][CH3:25])[C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1)[CH3:22]
Reactant: CCOC(=O)c1sc(O)nc1C(F)(F)F
Reactant: CCNCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(N(CC)CC)nc1C(F)(F)F
Temperature: 163 °C
Reaction time: 14 h
Yield: 42.2 %

Procedure:
A reaction vessel was charged with 96.4 g (400 mmol) of ethyl 2-hydroxy-4-trifluoromethyl-5-thiazolecarboxylate and 117 g (766 mmol) of phosphorus oxychloride and then cooled in an ice bath. To the cooled mixture was added 40 g of diethylamine. The reaction mixture was heated at reflux at 163° C. with stirring for about 14 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was poured into ice water and a solid precipitate was collected. The solid precipitate was dissolved in ethyl ether, washed with 5% sodium hydroxide, dried with calcium sulfate, and concentrated under reduced pressure to provide 50 g of residue. This residue was subjected to Kugelrohr distillation (100°-120° C. @ 0.5 mm Hg) to provide 3.5 g of a yellow liquid identified in Table I.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:4](I)[CH:3]=1.[F:18][C:19]([F:30])([F:29])[CH2:20][S:21][CH2:22][C:23]([OH:28])([CH2:26][CH3:27])[C:24]#[CH:25]>>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9])[N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[C:24]([C:23]([OH:28])([CH2:26][CH3:27])[CH2:22][S:21][CH2:20][C:19]([F:30])([F:18])[F:29])=[CH:25]2
Reactant: CS(=O)(=O)Nc1cc(C(F)(F)F)c(F)cc1I
Reactant: C#CC(O)(CC)CSCC(F)(F)F
Product: CCC(O)(CSCC(F)(F)F)c1cc2cc(F)c(C(F)(F)F)cc2n1S(C)(=O)=O

Procedure:
This compound was prepared using the general Sonagashira procedure as describe in General Procedures Example C, reacting N-(4-fluoro-2-iodo-5-trifluoromethyl-phenyl)-methanesulfonamide (0.57 g, 1.5 mmol) and 3-(2,2,2-trifluoro-ethylsulfanylmethyl)-pent-1yn-3-ol (0.32 g, 1.5 mmol) to yield the title compound as a brown oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)=[N:2]1.[OH-].[Na+].[Br-:21].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.Cl>ClCCl>[Br:21][C:5]1[NH:1][N:2]=[C:3]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc[nH]n2)CC1
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(Br)n2)CC1
Yield: 86.6 %

Procedure:
To a stirred solution of tert-butyl 4-(1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (22 g, 87.19 mmol) in dichloromethane (250 mL) was added sodium hydroxide 2N (131 mL, 261.58 mmol). The reaction mixture was vigorously stirred with mechanical stirring and a solution of benzyltrimethylammonium tribromide (37.4 g, 95.91 mmol) in dichloromethane (250 mL) was then added dropwise, keeping temperature around 15° C. The reaction mixture was left to stir at room temperature for 1 h and 2N HCl was added to give a pH of 5 (keeping temperature around 15° C.). The phases were decanted and the organic phase was washed with H2O (2×1 L), dried over MgSO4, filtered and concentrated to afford tert-butyl 4-(5-bromo-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (25.00 g, 87%) as an off-white solid: 1H NMR Spectrum; (CDCl3) 1.46 (9H, s), 1.67-1.84 (2H, m), 1.90-2.13 (2H, m), 2.77-2.96 (2H, m), 2.98-3.10 (1H, m), 3.94-4.35 (2H, m); Mass Spectrum [M+H]+=no mass ion.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][O:11]1.[NH2:18][C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[N:6]=1)=[O:17])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])[NH2:22]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1ccc(Br)c(OCC2CCCO2)n1
Product: CC(C)C[C@H](NC(=O)c1ccc(Br)c(OCC2CCCO2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 a) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=416.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:41])([CH3:40])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([CH3:39])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([NH:28]C(=O)OC(C)(C)C)=[CH:27][C:21]=3[S:20](=[O:37])(=[O:36])[N:19]=2)[C:8]1=[O:38].[ClH:42]>O1CCOCC1>[ClH:42].[NH2:28][C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:18]([C:9]3[C:8](=[O:38])[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:2]([CH3:1])([CH3:40])[CH3:41])([CH3:39])[C:16]4[C:11]([C:10]=3[OH:17])=[CH:12][CH:13]=[CH:14][CH:15]=4)=[N:19][S:20](=[O:37])(=[O:36])[C:21]=2[CH:27]=1
Reactant: CC(C)(C)CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Yield: 54 %

Procedure:
A solution of Example 37A (0.775 g, 1.33 mmol) in 4M hydrochloric acid in 1,4-dioxane (10 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give the title compound (0.374 g, 54%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[CH:9]=1)=[O:4].O.[OH-].[Na+]>O1CCOCC1>[N+:16]([C:12]1[CH:11]=[C:10]([N:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[C:6](=[O:19])[NH:7]2)[CH:15]=[CH:14][CH:13]=1)([O-:18])=[O:17]
Reactant: COC(=O)c1cn(-c2cccc([N+](=O)[O-])c2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cn(-c2cccc([N+](=O)[O-])c2)[nH]c1=O
Yield: 62.6 %

Procedure:
1-(3-Nitrophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid methyl ester (1.43 g, 0.005 mole) (Taylor A. W. et al, Tetrahedron, 1987, 43 (3), 607-616) in 1,4-dioxane (100 ml) and water (100 ml) was treated with sodium hydroxide (2 g, 0.05 mole) and heated under reflux for 6 hours. The mixture was allowed to cool then concentrated to a small volume in-vacuo, and acidified with concentrated hydrochloric acid. The resulting solid was filtered off and dried in-vacuo to give the title compound as an off-white solid (0.78 g, 60%). M.S. (−ive ion electrospray) m/z 248 ([M−H]−, 25%), 276 (100%).
Reaction SMILES: CI.[ClH:3].[CH3:4][NH:5][CH2:6][CH2:7][S:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[C:25](=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:3].[CH3:4][N:5]([CH3:25])[CH2:6][CH2:7][S:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=C([O-])[O-]
Reactant: CNCCSc1nc2ccccc2cc1-c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CI
Product: CN(C)CCSc1nc2ccccc2cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl iodide (0.85 g.) was added to a mixture of 2-(2-methylaminoethylthio)-3-phenylquinoline hydrochloride (1.65 g.) and potassium carbonate (1.65 g.) in dry ethanol (50 ml.) at ambient temperature. The mixture was stirred at ambient temperature for 3 hr. and the solvent was then evaporated. The residue was dissolved in water (50 ml.) and extracted with diethyl ether (3×25 ml.). The diethyl ether extract was washed with brine (25 ml.), dried (MgSO4), and the solvent evaporated. The residual oil was chromatographed on basic alumina (75 g., Brockmann Grade III), eluted with increasing concentrations of methylene dichloride in petroleum ether. The eluate with 50% v/v methylene dichloride in petroleum ether was evaporated. The residue was dissolved in diethyl ether (25 ml.) and ethereal hydrogen chloride added until precipitation was complete. The mixture was filtered and the solid residue was crystallised from methanol-ethyl acetate to give 2-(2-dimethylaminoethylthio)-3-phenylquinoline hydrochloride, m.p. 196°-8°.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([CH2:15][CH3:16])([F:14])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:50][C:45]2[CH:46]=C[CH:48]=[N:49][C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN1CC(N)C1>>[CH:1]1([N:7]2[CH2:13][C:12]([CH2:15][CH3:16])([F:14])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:50][CH:45]5[CH2:44][N:49]([CH3:48])[CH2:46]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CC(N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CCC1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)NC4CN(C)C4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylazetidin-3-amine hydrochloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.71-0.95 (m, 1H) 0.89 (t, J=7.3 Hz, 3H) 1.07-1.92 (m, 12H) 2.29 (s, 3H) 3.03 (t, J=7.1 Hz, 2H) 3.26 (s, 3H) 3.51-3.76 (m, 1H) 3.58 (t, J=7.2 Hz, 2H) 3.76-3.87 (m, 1H) 3.95 (s, 3H) 4.44 (m, 1H) 7.49 (d, J=8.3 Hz, 1H) 7.52 (s, 1H) 7.78 (s, 1H) 8.11 (s, 1H) 8.33 (d, J=8.6 Hz, 1H) 8.63 (d, J=6.8 Hz, 1H). [M+H] calc'd for C28H38FN7O3, 540. found 540.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:7]([F:17])=[CH:6][CH:5]=2.[Sn].Cl>C(O)(=O)C>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:17])[C:8]=2[N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[NH:3]1
Reactant: Cc1cc2c(N3CCOCC3)c(F)ccc2[nH]1
Agent: Cl
Agent: [Sn]
Solvent: CC(=O)O
Product: CC1Cc2c(ccc(F)c2N2CCOCC2)N1
Yield: 53.9 %

Procedure:
2-Methyl-5-fluoro-4-morpholinoindole (138 g) was dissolved in 1.5 l of acetic acid. To this solution was added 200 g of metal tin and the mixture was under reflux of acetic acid. During reflux 1.5 l of concentrated hydrochloric acid was added dropwise in 1 hour. After completion of addition, the mixture was allowed to react for 2 hours at the same temperature as above. After completion of reaction, the solvent was distilled off under reduced pressure. To the residue was added 1 l of water and the solution was adjusted to pH 13 with a 20% aqueous sodium hydroxide solution followed by adding 1 l of ether. After stirring insoluble substances were removed by filtration. An ether layer was separated from the filtrate and dried over anhydrous potassium carbonate. Removal of ether by distillation gave 75 g of 2-methyl-4-morpholino-5-fluoroindoline.