Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:27]#[N:28])[N:5]([C:7]2[CH:26]=[CH:25][C:10]([CH2:11][N:12]3[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH3:21])=[C:15]4[N:14]=[C:13]3[S:22][CH2:23][CH3:24])=[CH:9][CH:8]=2)[CH:6]=1.[N-:29]=[N+:30]=[N-:31].[Na+].Cl.C(N(CC)CC)C.Cl>CN1CCN(C)C1=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:27]2[NH:31][N:30]=[N:29][N:28]=2)[N:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][N:12]3[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH3:21])=[C:15]4[N:14]=[C:13]3[S:22][CH2:23][CH3:24])=[CH:25][CH:26]=2)[CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCSc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)cc2C#N)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCN(C)C1=O
Product: CCSc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(Cl)cc2-c2nnn[nH]2)cc1
Temperature: 135 °C
Reaction time: 24 h
Yield: 81.9 %

Procedure:
To a mixture of 3-[4-(4-chloro-2-cyano-1-pyrrolyl)benzyl]-2-ethylthio-7-methyl-3H-imidazo[4,5-b]pyridine (846 mg) in 1,3-dimethyl-2-imidazolidinone (10 ml) was added sodium azide (539 mg) and triethylamine hydrochloride (1.425 g) and stirred at 135° C. for 24 hours. The reaction mixture was poured into ice-water and the pH value was adjusted to 4 with 7% hydrochloric acid, extracted with ethyl acetate (twice) and the organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was crystallized from methyl cyanide and washed hot methyl cyanide to give 3-[4-[4-chloro-2-(1H-tetrazol-5-yl)-1-pyrrolyl]-benzyl]-2-ethylthio-7-methyl-3H-imidazo[4,5-b]pyridine(766 mg) as a brown solid. mp: 88°-90° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:24]([C:26]1[CH:27]=[C:28]([C:36](Cl)=[O:37])[C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)#[N:25]>C(Cl)Cl>[C:24]([C:26]1[CH:27]=[C:28]([C:36]([N:10]([CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:12][CH:13]=[CH2:14])[CH3:11])=[O:37])[C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)#[N:25]
Reactant: C=CCC(CNC)c1ccc(F)cc1
Reactant: N#Cc1cc(C(=O)Cl)c2ccccc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC(CN(C)C(=O)c1cc(C#N)cc2ccccc12)c1ccc(F)cc1
Yield: 80.5 %

Procedure:
[2-(4-Fluorophenyl)pent-4-en-1-yl]methylamine (1.0 g, 5.2 mmol) was dissolved in CH2Cl2 and stirred at 0° C. during addition of DIPEA (1.5 g, 11.4 mmol) and 3-cyano-1-naphthoyl chloride (Method 11; 1.1 g, 5.17 mmol). The mixture was stirred with cooling for a short while and then stirred at room temperature for 2 h. The mixture was washed twice with water, once with an aqueous solution of KHSO4, and then with brine. The solvent was removed by evaporation and the residue flash chromatographed on silica gel (methanol-CH2Cl2, 5:95). There was obtained 1.55 g (80%) of 3-cyano-N-[2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-1-naphthamide as an oil. 1H NMR (400 MHz, CDCl3): 2.1-4.9 (cm, 8H), 5.0-5.1 (m, 2H), 5.6-5.8 (m, 1H), 6.4-8.0 (cm, 9H), 8.2 (s, 1H).
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([F:19])[C:9]([O:20][CH:21]([CH3:23])[CH3:22])=[C:8]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([N:31]4[CH2:40][CH2:39][C:38]5[N:37]=[C:36]([CH2:41][CH3:42])[C:35]([C:43]([O:45]C)=[O:44])=[CH:34][C:33]=5[C:32]4=[O:47])[CH2:27][CH2:26]3)[CH:7]=2)[CH2:5][CH2:4]1.Cl.O>CO>[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([F:19])[C:9]([O:20][CH:21]([CH3:23])[CH3:22])=[C:8]([CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([N:31]4[CH2:40][CH2:39][C:38]5[N:37]=[C:36]([CH2:41][CH3:42])[C:35]([C:43]([OH:45])=[O:44])=[CH:34][C:33]=5[C:32]4=[O:47])[CH2:29][CH2:30]3)[CH:7]=2)[CH2:5][CH2:4]1
Reactant: CCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)c(F)c3OC(C)C)CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)c(F)c3OC(C)C)CC1)CC2
Reaction time: 2 h
Yield: 92.5 %

Procedure:
2M aqueous sodium hydroxide solution (20 mL) was added to a solution of methyl 6-(1-((6-cyclopropyl-2,4′-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-2-ethyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (8.03 g) in methanol (25 mL) at 70° C. The mixture was stirred at the same temperature under nitrogen atmosphere for 2 hours. The mixture was neutralized with 1M hydrochloric acid at room temperature and added to water (100 mL). The mixture was stirred at 70° C. for 30 minutes and at room temperature for 2 hours to give colorless crystals. After filtration, the crystals were dissolved in ethanol. The solution was filtrated and the filtrate was concentrated in vacuo to give a colorless solid. The solid was recrystallized from ethanol-water (45 mL-130 mL) to give the title compound (7.26 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(=O)(O)[O-].[Na+]>C(O)C.[Cl-].[Na+].O>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])=[C:18]([F:23])[CH:17]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: Nc1ccc(Cl)cc1F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Cl)cc1F

Procedure:
To 3.5 g of 4-chloro-6-fluoro-[1.7]naphthyridine-3-carbonitrile in 100 mL of absolute ethanol was added 2.3 mL of 4-chloro-2-fluoroaniline. After stirring the reaction under an inert atmosphere for 24 hours, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals were filtered and washed with water. The product was then recrystallized from chloroform/ethyl acetate/hexanes. Drying in vacuo yielded 1.9 (40%) of 4-(4-chloro-2-fluoro-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile as yellow needles: melting point 249-252° C.; mass spectrum (m/e): M+H 316.9.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[N:8][N:7]=2)=[CH:2]1.[CH2:15](O)[CH2:16][CH2:17][CH2:18][OH:19].C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>C(OCC)(=O)C>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][O:13][C:12](=[O:14])[CH2:11][N:10]1[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][N:8]=[N:9]1
Reactant: OCCCCO
Reactant: O=C(O)Cn1nnnc1-c1ccsc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(Cn1nnnc1-c1ccsc1)OCCCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
To a suspension of 1 g (4.76 mM) of [5-(3-thienyl) tetrazol-1-yl]acetic acid and 514 mg (5.71 mM) of 1,4-butanediol in 20 ml of ethyl acetate was added 1.08 g (5.23 mM) of dicyclohexylcarbodiimide at room temperature. After the mixture was stirred at room temperature for 30 min, a small amount of acetic acid was added to the mixture and then was stirred for 30 min. The mixture was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent; chloroform/ethyl alcohol=30/1) for separation and purification, to give 520 mg (yield 38.7%) of [5-(3-thienyl)tetrazol-1-yl]acetic acid 4-hydroxybutyl ester.
Reaction SMILES: [F:1][C:2]([O:10][C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])([C:6]([F:9])([F:8])[F:7])[C:3]([OH:5])=[O:4].[Cl-].[C:22]1([S+:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(C(C)=O)C(C)C>ClCCl>[F:1][C:2]([O:10][C:11]([F:19])([F:20])[C:12]([F:18])([F:17])[C:13]([F:14])([F:15])[F:16])([C:6]([F:9])([F:8])[F:7])[C:3]([O-:5])=[O:4].[C:35]1([S+:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)CC(C)C
Solvent: ClCCl
Product: O=C([O-])C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Yield: 35.4 %

Procedure:
To 6.6 g (0.02 mol) of 2,3,3,3-tetrafluoro-2-(1,1,2,2,3,3,3-heptafluoropropoxy)propionic acid were added an amount (0.03 mol) of triphenylsulfonium chloride aqueous solution, 60 g of methyl isobutyl ketone, and 25 g of dichloromethane. An organic layer was taken out, and washed with 50 g of water three times. After the solvent was distilled off in vacuum, the residue was added to diisopropyl ether for crystallization. On filtration and drying, 4.2 g of white crystals was obtained (yield 35%). The compound thus obtained was analyzed by spectroscopy.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][CH:49]([O:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH:67]([C:69]1[CH:83]=[CH:82][C:72]([CH2:73][NH:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[CH:71][CH:70]=1)=O>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][CH:49]([O:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:67]([C:69]3[CH:83]=[CH:82][C:72]([CH2:73][NH:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:78])[CH3:79])=[CH:71][CH:70]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCC(Oc3ccccc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(N4CCC(Oc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 26.4 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-phenoxypiperidin-1-yl)pyridin-2-amine (75 mg, 0.19 mmol), DMF (0.20 mL), ethanol (1.00 mL), 1M Na2S2O4 (3 eq, 0.58 mmol, 0.58 mL) and tert-butyl N-(4-formylbenzyl)carbamate (1.1 eq, 0.21 mmol, 49 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (29 mg, 20%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.41 (s, 9H, C(CH3)3), 1.84-1.90 (m, 2H, 2× piperidine CHAHB), 2.16-2.19 (m, 2H, 2× piperidine CHAHB), 3.59-3.64 (m, 2H, 2× piperidine NCHAHA), 3.87-3.91 (m, 2H, 2× piperidine NCHAHA), 4.19 (d, J=5.9 Hz, 2H, CH2NH), 4.70 (septet, J=3.9 Hz, 1H, piperidine CH), 6.94 (t, J=7.3 Hz, 1H, phenyl H-4), 7.04 (d, J=7.8 Hz, 2H, phenyl H-3′ & H-5′), 7.31 (dd, J=8.6, 7.4 Hz, 2H, phenyl H-3 & H-5), 7.40 (d, J=8.3 Hz, 2H, phenyl H-2 & H-6), 8.13 (d, J=8.1 Hz, 2H, phenyl H-2′ & H-6′), 8.24 (s, 1H, imidazo[4,5-b]pyridine H-5), 13.45 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH:8]=[CH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.CN(P(N(C)C)(N(C)C)=O)C.[C:25]1([Mg]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH:8]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1C=CCOc2ccc(Br)cc21
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: O=C1CC(c2ccccc2)COc2ccc(Br)cc21
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of 7-bromobenzo[b]oxepin-5(2H)-one (1.33 g, 5.6 mmol), CuBr—SMe2 (60 mg, 0.3 mmol) and HMPA (2.058 g, 11.5 mmol) in THF (30 mL) was added phenylmagnesium bromide (3.0 M, 3.7 mL) at −78, the mixture was stirred at −78 for 1 hour. The mixture was quenched by HCl (10%, 5 mL), extracted with ethoxyethane, and then washed with NaHCO3, brine, dried over Na2SO4, concentrated and purified by column chromatography to give 7-bromo-3-phenyl-3,4-dihydrobenzo[b]oxepin-5(2H)-one (300 mg, 17%). 1H-NMR(CH2D2): 3.11 (m, 2H), 3.49 (m, 1H), 4.28 (m, 2H), 6.93 (m, 1H), 7.17 (m, 1H), 7.23 (m, 4H), 7.45 (m, 1H), 7.83 (m, 1H)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9](Cl)=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14])(=[O:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1c(C)ccnc1Cl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1c(C)ccnc1-c1cccnc1

Procedure:
By carrying out the operation analogously to example 1, starting from 2-chloro-4-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VI, and 3-pyridineboronic acid, the desired product is obtained in the form of a white foam (yield=27%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][S:8]([CH3:10])=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:29])[CH2:19][N:20]2[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]2[C:26]([OH:28])=[O:27])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:29])[CH2:19][N:20]2[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]2[C:26]([O:28][CH2:7][S:8][CH3:10])=[O:27])=[CH:16][CH:17]=1
Reactant: CS(C)=O
Reactant: Cc1ccc(C(=O)O)n1CC(O)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCOC(=O)c1ccc(C)n1CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
A solution of oxalyl chloride (0.3 mL, 3.5 mmol) in CH2Cl2 (0.5 mL) was added dropwise to a solution of DMSO (0.34 mL, 4.8 mmol) in CH2Cl2 (1.5 mL) at −65° C. and stirred for 10 min. The resultant solution was added to a suspension of 1-[2-(4-fluorophenyl)-2-hydroxyethyl]-5-methyl-1H-pyrrole-2-carboxylic acid (211 mg, 0.8 mmol) in CH2Cl2 (10 mL) at −65° C. The resultant suspension was stirred at −65° C. for 15 min, then triethylamine (1.12 mL, 8.0 mmol) was added drop-wise. Once the addition was complete the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was then quenched by the addition of CH2Cl2 (50 mL) and water (10 mL), the organic layer was separated and the aqueous extracted with further CH2Cl2 (10 mL). The organic layers were combined and washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a brown solid. The solid was purified by flash column chromatography (Biotage SP4, 40 g cartridge, hexane 1 CV, 0-50% EtOAc/hexanes 10 CV) to give (methylsulfanyl)methyl 1-[2-(4-fluorophenyl)-2-oxoethyl]-5-methyl-1H-pyrrole-2-carboxylate as a off-white solid (162 mg, 62%). 1H NMR (400 MHz, CDCl3): δ 2.19 (s, 3H), 2.22 (s, 3H), 5.19 (s, 2H), 5.76 (s, 2H), 6.06 (dd, 1H, J 3.9, 0.7 Hz), 7.06 (d, 1H, J 3.9 Hz), 7.13-7.24 (m, 2H), 8.06 (dd, 2H, J 9.0, 5.3 Hz). ESI-MI m/z [M+H]+ 321.80.
Reaction SMILES: [OH:1][PH:2]([CH2:4][CH:5]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[O:3].[C:22](O)([CH3:25])([CH3:24])[CH3:23].C(N=C=NCCCN(C)C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[C:22]([O:3][PH:2]([CH2:4][CH:5]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[O:1])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)O
Reactant: CC(C)(C)OC(=O)CCC(C[PH](=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCC(C[PH](=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a solution of di-tert-butyl 2-[(hydroxyphosphinyl)methyl]pentane-1,5-dioate (315 g, 0.977 mol) in dichloromethane (1000 ml) cooled in an ice bath and under nitrogen were added tert-butanol (123.1 g, 1.66 mol), 4-dimethylaminopyridine (1 g, 8.2 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (281 g, 1.47 mol). The reaction was allowed to stir overnight. Water was added to the reaction mixture and the dichloromethane layer was retained and dried, and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography and the desired product was eluted with 1:1 to 2:3 hexane/ethyl acetate. The fractions containing product were concentrated under reduced pressure leaving a clear oil (260 g, 70%). 1H NMR (CDCl3): δ1.4 (m, 27H), 1.8 (m, 1H), 1.9 (m, 2H), 2.1 (m, 1H), 2.3 (m, 2H), 2.7-2.8 (m, 1H), 6.7 & 8.0 (d, 1H, the P—H).
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)[C:37]=1[C:38](O)=[O:39].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)[C:37]=1[C:38]([N:3]1[CH2:4][CH2:5][C@@H:6]2[C@@H:1]([N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7]2)[CH2:2]1)=[O:39]
Reactant: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: O=C(c1c(F)cccc1-n1nccn1)N1CC[C@H]2CN(c3cnc4ccccc4n3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)quinoxaline (Intermediate 3) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 15) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C23H20FN7O, 429.46; m/z found 430.2 [M+H]+. 1H NMR (CD3OD): 8.42-7.97 (m, 2H), 7.88-7.44 (m, 5H), 7.39-6.20 (m, 3H), 5.08-4.67 (m, 1H), 4.41-3.44 (m, 6H), 3.25-3.07 (m, 1H), 2.39-1.86 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH:16]=[C:15]([Cl:18])[CH:14]=[CH:13][C:12]=2[C:11](=[O:19])[C:10]2=[CH:20][CH:21]=[CH:22][N:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23]N1C(=O)CCC1=O.[Al]>C1COCC1>[CH2:1]([N:8]1[C:17]2[CH:16]=[C:15]([Cl:18])[CH:14]=[CH:13][C:12]=2[C:11](=[O:19])[C:10]2=[CH:20][CH:21]=[C:22]([Cl:23])[N:9]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1c2ccc(Cl)cc2n(Cc2ccccc2)n2cccc12
Agent: [Al]
Solvent: C1CCOC1
Product: O=c1c2ccc(Cl)cc2n(Cc2ccccc2)n2c(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
5-Benzyl-7-chloropyrrolo[1,2-b]cinnolin-10(5H)-one (4.5 g) was taken up in 50 ml of THF and a catalytic amount of dibenzoyl eroxide was added. N-chlorosuccinimide (1.95 g) was added portionwise over a period of 10 min. The flask was covered with aluminum foil and the mixture stirred at room temperature overnight under N2. The reaction mixture was concentrated and the residue taken up in chloroform and extracted with H2O and brine. The organic layer was then dried (MgSO4), charcoaled, filtered and concentrated to a green semisolid. This was purified by HPLC (silica, dichloromethane) to give a light green powder which was recrystallized from ethanol to yield 2.3 g of green crystals, mp 134°-136°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH2:11].N1C=CC=CC=1.[C:18](Cl)(Cl)=[O:19]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N:11]=[C:18]=[O:19]
Reactant: COc1cc(N)c(F)cc1C
Reactant: O=C(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(N=C=O)c(F)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Fluoro-5-methoxy-4-methyl-phenylamine (78 mg, 0.50 mmol) was dissolved in 10 ml of toluene at room temperature. DMAP (1 eq, 61 mg), pyridine (1.3 eq, 0.06 ml) were added followed by phosgene (1.33 eq, 0.34 ml, 20% solution in toluene). The mixture was allowed to stir at room temperature for 3 hours, forming a fine white precipitate. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with dichloromethane and concentrated in vacuo again to give 1-fluoro-2-isocyanato-4-methoxy-5-methyl-benzene (90 mg, quantitative) as a clear oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:37])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]2[S:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[N:22][C:21]=2[CH3:35])=[CH:14][C:13]=1[CH3:36].I[CH2:39][CH3:40]>CS(C)=O.CCOCC>[CH3:7][O:8][C:9](=[O:37])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:39][CH3:40])[CH2:19][C:20]2[S:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)=[N:22][C:21]=2[CH3:35])=[CH:14][C:13]=1[CH3:36]
Reactant: CCI
Reactant: COC(=O)COc1ccc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCN(Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1C)c1ccc(OCC(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 58.9 %

Procedure:
A suspension of potassium carbonate (76 mg, 0.55 mmol), and (2-methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid methyl ester (225 mg, 0.50 mmol, example 18.2) in DMSO (3 ml) was treated with iodoethane (0.04 ml, 0.53 mmol) in DMSO (0.5 ml) and stirred for 19 h at RT. Again iodoethane (0.34 ml, 4.20 mmol) in 2 portions over 7 h was added. The reaction mixture was taken up in ether and washed with KHSO4-solution (10%). The organic phase was washed with NaCl (10%), dried (Na2SO4) and evaporated. Purification by flash chromatography (SiO2, n-heptane/AcOEt=9/1) gave 141 mg of pure (4-{ethyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-2-methyl-phenoxy)-acetic acid methyl ester, MS: 479.5 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][O:56][CH:57]([O:66][CH3:67])[CH2:58][NH:59][CH:60]1[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>CN(C=O)C>[CH:60]1([N:59]([CH2:58][CH:57]([O:66][CH3:67])[O:56][CH3:55])[C:16](=[O:18])[CH2:15][CH2:14][O:13][CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[C:8]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:6]=3[CH3:7])[CH:9]=2)[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1
Reactant: COC(CNC1CCCCC1)OC
Reactant: Cc1c(-c2cccc(CCOCCC(=O)O)c2)cnn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C)c2C)c1)C1CCCCC1)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(3-(1,5-dimethyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 37 Step ii)] (0.3 g) and DIPEA (0.545 mL) in DMF (4 mL) was added HATU (0.475 g) and the mixture was stirred at ambient temperature for 10 min. To this solution was added N-(2,2-dimethoxyethyl)cyclohexanamine (0.214 g) and the reaction mixture was stirred at ambient temperature for 2.5 h. The reaction mixture was poured onto water and extracted with ethyl acetate (2×100 mL). The organics were washed well with water, then brine and dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20-70% ethyl acetate in isohexane to afford the titled compound (0.185 g) as an oil. MS [M+H-MeOH]+=426 (MultiMode+) 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.33-7.27 (m, 1H), 7.22-7.17 (m, 2H), 7.12 (d, 1H), 3.84 (s, 3H), 3.79 (dt, 2H), 3.70 (dt, 2H), 3.40 (s, 6H), 3.37 (d, 1H), 3.30 (d, 1H), 2.94-2.88 (m, 2H), 2.74-2.65 (m, 2H), 2.38 (s, 3H), 1.86-1.73 (m, 2H), 1.73-1.59 (m, 3H), 1.53-1.19 (m, 5H), 1.14-1.02 (m, 1H).