Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[C@H:14]1([NH2:21])[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:20][C@H:17]2[CH2:18][CH2:19][C@H:14]([NH2:21])[CH2:15][CH2:16]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.21 g, 0.98 mmol) (Example 1, step 2), trans-cyclohexane-1,4-diamine (from Aldrich, 0.13 g, 1.2 mmol) and N,N-diisopropylethylamine (0.34 mL, 2.0 mmol) in isopropyl alcohol (3.3 mL) was heated at 90° C. for 2 h. The solvent in the resulting mixture was removed to give the desired product, which was used directly in the next step. LCMS calculated for C13H17N4O2S (M+H)+: m/z=293.1. Found: 293.0.
Reaction SMILES: [NH2:1][C@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[CH2:4][CH2:5][O:6][C:7]2([CH3:12])[CH3:11].[CH:13](OC(=O)C)=[O:14]>N1C=CC=CC=1>[CH3:11][C:7]1([CH3:12])[O:6][CH2:5][CH2:4][C@H:3]2[N:8]1[C:9](=[O:10])[C@@H:2]2[NH:1][CH:13]=[O:14]
Reactant: CC(=O)OC=O
Reactant: CC1(C)OCC[C@@H]2[C@@H](N)C(=O)N21
Solvent: c1ccncc1
Product: CC1(C)OCC[C@@H]2[C@@H](NC=O)C(=O)N21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of (6R,7R)-7-amino-2,2-dimethyl-1-aza-3-oxabicyclo[4.2.0]octan-8-one (300 mg) were added pyridine (0.25 ml) and freshly prepared acetic formic anhydride (0.38 ml) at 0° C. After stirring for 45 minutes at 0° C., the reaction mixture was evaporated in vacuo. The residue was dissolved in xylene and the solution was evaporated in vacuo. The residue was chromatographed on silica gel (6 g) eluting with a mixture of methylene chloride and methanol (25:1-10:1) to give (6R,7R)-2,2-dimethyl-7-formamido-1-aza-3-oxabicyclo[4.2.0]octan-8-one (378 mg) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([CH2:19][CH2:20][C:21](=[O:37])[C:22]2[S:23][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]([CH3:14])([CH3:13])[C:6]([O:8]C(C)(C)C)=[O:7].FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:18]=[C:17]([CH2:19][CH2:20][C:21](=[O:37])[C:22]2[S:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]([CH3:13])([CH3:14])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F)C(=O)O

Procedure:
2-(2-Fluoro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)-2-methylpropanoic acid is prepared from tert-butyl 2-(2-fluoro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate according to general procedure E using 17 equivalents of trifluoroacetic acid.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][C:5]12[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:6]1[C:7]([NH:9][C:10]2=[O:11])=[O:8])=O.[CH3:18][NH:19][CH2:20][CH2:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[CH:25]=[N:24][CH:23]=1>>[CH3:18][N:19]([CH2:20][CH2:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[CH:25]=[N:24][CH:23]=1)[CH2:1][CH2:3][CH2:4][C:5]12[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:6]1[C:7]([NH:9][C:10]2=[O:11])=[O:8]
Reactant: CC1=C(C)C2C(=O)NC(=O)C2(CCC=O)C=C1
Reactant: CNCCc1cncc2cc(OC)c(OC)cc12
Product: COc1cc2cncc(CCN(C)CCCC34C=CC(C)=C(C)C3C(=O)NC4=O)c2cc1OC

Procedure:
Prepared from 2-(2-formyl-ethyl)-5,6-dimethyl-phthalimide and 4-(2-methylamino-ethyl)-6,7-dimethoxy-isoquinoline analogously to Example 4.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14][CH2:15][CH2:16][CH3:17])[N:8]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=1)[C:7]2=[O:55].[CH2:56]([O:63][C:64](Cl)=[O:65])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>CN(C=O)C>[CH2:14]([C:9]1[N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:7](=[O:55])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([NH:3][C:64]([O:63][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[O:65])[CH:5]=2)[N:10]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1nc2ccc(N)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2ccc(NC(=O)OCc3ccccc3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 3 h
Yield: 62 %

Procedure:
To a suspension of 4 mg (0.12 mmol) of 80% NaH in oil in 1 mL of dry DMF under nitrogen was added at 0° C. a solution of 69 mg (0.1 mmol) of the 6-aminoquinazoline from Example 40. A bright blue solution was formed. After 0.5 hours 18.8 mg (0.1 mmol) of benzylchloroformate was added via syringe. The blue colour rapidly dissipated and the reaction mixture was stirred for 3 hours while allowing the temperature to rise to room temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in 25 mL of EtOAc and 5 mL of water. The aqueous phase was extracted with EtOAc (2×5 mL) and the combined organic phases were washed with water (1×5 mL) and brine (1×5 mL) and dried over MgSO4. The mixture was filtered and concentrated in vacuo and the residue was purified by flash chromatography over silica gel eluting with 30% EtOAc/hexane to give 51.7 mg (0.62 mmol), 62% yield. 1H-NMR (CDCl3 300 MHz): 0.88 (t, 3H, J=7.3 Hz), 1.32 (m, 2H), 1.68 (m, 2H), 2.60 (3 line m, 2H, J= 8.41 Hz), 5.19 (s, 2H), 5.29 (bs, 2H), 6.90 (m, 8H), 7.09 (d, 1H, J=8.2 Hz), 7.2-7.52 (m, 18H), 7.65 (d, 1H, J=8.8 Hz), 7.91 (m, 1H), 8.19 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[N:29]#CBr>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2([CH2:15][CH2:14][N:13]([C:16]#[N:29])[CH2:12][CH2:11]2)[CH2:9]1
Reactant: N#CBr
Reactant: CN1CCC2(CC1)CN(c1ccccc1Cl)c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC2(CC1)CN(c1ccccc1Cl)c1ccccc12
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To 1.0 g of 1-(2-chlorophenyl)-1'-methylspiro[indoline-3,4'-piperidine] of Example 17 in 16 ml of dry chloroform is added 2.4 g of anhydrous potassium carbonate and 0.73 g of cyanogen bromide. The reaction is stirred 7 hours at room temperature and then is filtered through paper. Approximately one ml of methanol is added and the solution is rotary evaporated to a glass. The glass is chromatographed on 80 cc of silica gel with 1:1, ether:dichloromethane to give a crystalline solid. The solid is recrystallized thrice from acetone-hexane to give a solid of 1-(2-chlorophenyl)-1'-cyanospiro(indoline-3,4'-piperidine), mp 157.5°-159.5° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30](Br)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[C:12]([O:40][CH3:41])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:42]([O:46][C:47](=[O:55])[CH2:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)([CH3:45])([CH3:44])[CH3:43]>>[C:42]([O:46][C:47](=[O:55])[CH2:48][N:49]1[CH2:50][CH2:51][N:52]([C:30]2[CH:31]=[CH:32][C:24]([NH:23][C:21]3[C:20]([C:36]([F:37])([F:39])[F:38])=[CH:19][N:18]=[C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([CH2:9][P:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[O:8])=[CH:11][C:12]=4[O:40][CH3:41])[N:22]=3)=[C:25]3[C:29]=2[CH2:28][N:27]([CH3:34])[C:26]3=[O:35])[CH2:53][CH2:54]1)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)CN1CCNCC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(CC(=O)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 199 using Diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate and piperazine-1-acetic acid tert-butyl ester. MS (ES+): m/z 778.42 (100) [MH+]; HPLC: tR=0.86 min (UPLC, purity).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:9]([F:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[C:13]([F:18])[C:12]=2[F:19])[N:7]=[C:6]([C:20]([O:22]C)=[O:21])[C:5]=1[Cl:24].Cl>CO>[NH2:3][C:4]1[C:9]([F:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[C:13]([F:18])[C:12]=2[F:19])[N:7]=[C:6]([C:20]([OH:22])=[O:21])[C:5]=1[Cl:24]
Reactant: COC(=O)c1nc(-c2ccc(I)c(F)c2F)c(F)c(N)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1c(F)c(-c2ccc(I)c(F)c2F)nc(C(=O)O)c1Cl
Temperature: 23 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
A 2 M solution of aqueous sodium hydroxide (270 L, 0.54 mmol, 2.0 equiv) was added to a stirred suspension of methyl 4-amino-3-chloro-6-(2,3-difluoro-4-iodophenyl)-5-fluoropicolinate (120 mg, 0.27 mmol, 1.0 equiv) in methanol (2.7 mL) at 23° C. The heterogeneous white mixture was stirred at 23° C. for 18 h. The reaction mixture was adjusted to approximately pH 4 via dropwise addition of concentrated hydrochloric acid and concentrated via rotary evaporation. The residue was dissolved in dichloromethane (250 mL), passed through a hydrophobic membrane phase separator, dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a white powder (110 mg, 92%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4](CC2C=CC=CC=2)[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[Cl:25][CH2:26][CH2:27][N:28]=[C:29]=[O:30]>C(OCC)(=O)C>[Cl:25][CH2:26][CH2:27][NH:28][C:29]([NH:1][CH2:2][C:3]1([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:7](=[O:9])[C:6]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][NH:4]1)=[O:30]
Reactant: O=C=NCCCl
Reactant: NCc1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(NCCCl)NCC1(Cc2ccccc2)CC(=O)C(OCc2ccccc2)=CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 185.7 %

Procedure:
To a suspension of 48.0 g (0.15 mol) of 2-(aminomethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)-pyridinone in 1.5 l of ethyl acetate was added 12.8 ml (0.15 mol) of 2-chloroethylisocyanate. The mixture was stirred overnight at room temperature, the product filtered off by suction, washed with ethyl acetate, and dried in vacuo, yielding 59.6 g of the title compound, melting point 130° C.
Reaction SMILES: [CH2:1]([P:3]([CH2:10][CH2:11][CH2:12][OH:13])(=[O:9])[O:4][CH2:5][CH2:6]CC)[CH3:2].C(O)C[OH:16]>C([O-])(C([O-])=O)=O.C([O-])(C([O-])=O)=O.O=[Ti+2].[K+].[K+]>[CH2:1]([P:3]([CH2:10][CH2:11][CH2:12][OH:13])(=[O:9])[O:4][CH2:5][CH2:6][OH:16])[CH3:2]
Reactant: OCCO
Reactant: CCCCOP(=O)(CC)CCCO
Agent: O=[Ti+2]
Agent: O=C([O-])C(=O)[O-]
Agent: [K+]
Product: CCP(=O)(CCCO)OCCO
Temperature: 200 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
To 416 g (2 mol) of butyl ethyl(3-hydroxypropyl)phosphinate (produced as in Example 11) are added 155 g (2.5 mol) of ethylene glycol and 0.4 g of potassium titanyloxalate, followed by stirring at 200° C. for 2 h. Volatiles are distilled off by gradual evacuation to leave 439 g (98% of theory) of 2-hydroxyethyl ethyl(3-hydroxypropyl)phosphinate.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[N:4]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:26]=1[C:27](Cl)=[O:28]>C1COCC1>[F:24][C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:26]=1[C:27]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[N:4]=1)=[O:28]
Reactant: CNc1cccc(OC2CCN(C)CC2)n1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCC(Oc2cccc(N(C)C(=O)c3c(F)cc(F)cc3F)n2)CC1
Temperature: 55 °C

Procedure:
Dissolve the above amine product in THF (6 mL), add triethylamine (219 mg, 0.29 mL, 2.08 mmol) and 2,4,6-trifluorobenzoyl chloride (303 mg, 1.56 mmol) sequentially, heat at 55° C. overnight. Quench with 0.1N NaOH, extract with methylene dichloride three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 3.5% 2M NH3-methanol in methylene dichloride provides 204 mg (43% two-step yield) of the title compound as a colorless oil: mass spectrum (ion spray): m/z=380.1 (M+1); 1H NMR (CDCl3, ppm): 7.47 (t, 1H), 6.53 (m, 4H), 4.74 (m, 1H), 3.48 (s, 3H), 2.71 (m, 2H), 2.32 (s, 3H), 2.25 (m, 2H), 1.91 (m, 2H), 1.72 (m, 2H). Mono-hydrochloride salt: Anal. calc for C19H20F3N3O2.HCl.0.5H2O: C, 53.72; H, 5.22; N, 9.89. Found: C, 53.84; H, 5.04; N, 9.73.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:29]=[N:28][C:13]3[N:14]([CH2:26][CH3:27])[C:15]4[N:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:16]=4[N:17]([CH3:20])[C:18](=[O:19])[C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[Cl:25][C:23]1[CH:22]=[CH:21][C:16]2[N:17]([CH3:20])[C:18](=[O:19])[C:12]3[CH:11]=[C:10]([CH2:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:3][CH:4]=4)[CH:29]=[N:28][C:13]=3[N:14]([CH2:26][CH3:27])[C:15]=2[N:24]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCN1c2ncc(CCc3ccc(N)cc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1c2ncc(CCc3ccc(NS(C)(=O)=O)cc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-[2-(4-aminophenyl)ethyl]-2-chloro-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (16 mg, 0.04 mmol) and 6 μL of pyridine in dichloromethane at 0° C. was added 5 μL of methanesulfonyl chloride. The reaction mixture was allowed to stir at room temperature overnight. The orange reaction mixture was then concentrated to dryness and the product was purified by flash chromatography, eluting with methanol/dichloromethane, and recrystallization from ethanol/hexanes to give 6 mg of the title compound, m.p. 199°-204° C.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([OH:21])[CH2:20][O:19][CH2:18]3)=[CH:13][CH:12]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([CH:23]=[O:24])=[CH:5][NH:6]2.CC(=CC)C.Cl([O-])=[O:31].[Na+].O.OP([O-])(O)=O.[Na+]>C(#N)C.O.C(O)(C)(C)C>[F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([OH:21])[CH2:20][O:19][CH2:18]3)=[CH:13][CH:12]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([C:23]([OH:31])=[O:24])=[CH:5][NH:6]2
Reactant: O=Cc1c[nH]c2cc(F)c(-c3ccc(C4(O)COC4)cc3)c(F)c12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(F)c(-c3ccc(C4(O)COC4)cc3)c(F)c12
Temperature: 0 °C
Reaction time: 5 h
Yield: 10.4 %

Procedure:
A solution of 4,6-difluoro-5-[4-(3-hydroxyoxetan-3-yl)phenyl]-1H-indole-3-carbaldehyde (38 mg, 0.12 mmol) was dissolved in acetonitrile (1 mL) and warm tert-butanol (0.3 mL). The reaction mixture was treated with 2-methyl-2-butene (0.3 ml), cooled to 0° C., and treated with a solution of sodium chlorite (199 mg, 2.36 mmol) and sodium phosphate monobasic hydrate (332 mg, 2.41 mmol) in water (1 mL) via addition funnel. The ice bath was removed, and the reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction mixture was diluted with water (2 mL) and NH4Cl (2 mL). The product was extracted with EtOAc (3×20 mL). The organic layer was concentrated in vacuo to give the crude product, which was purified using prep-HPLC to give the title compound (4.3 mg). MS (ES+) 346.0 (M+H)+. Retention time: 2.04 min. Column: Waters Atlantis dC18 4.6×50 mm, 5 μm. Modifier: TFA 0.05%. Gradient: 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. Flow: 2.0 mL/min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C([Li])CCC.CN(C)[CH:22]=[O:23].[BH4-].[Na+]>O.CO.C(OCC)C>[O:8]([C:5]1[N:6]=[CH:7][C:2]([CH2:22][OH:23])=[CH:3][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccc(Oc2ccccc2)nc1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: OCc1ccc(Oc2ccccc2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 356.9 %

Procedure:
To a diethyl ether (30.0 mL) solution of 5-bromo-2-phenoxy-pyridine (1.02 g, 4.08 mmol) described in Manufacturing Example 40-1-1 was added dropwise n-butyl lithium (2.55 M n-hexane solution, 1.92 mL, 4.90 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 30 minutes at −78° C. Thereafter, N,N-dimethylformamide (378 μL, 4.90 mmol) was added dropwise, which was stirred for 10 minutes at −78° C. Then, sodium borohydride (309 mg, 8.16 mmol) and methanol (15.0 mL) were added, which was stirred for 20 minutes at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1) to obtain the title compound (2.93 g, 66.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:22])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Reactant: CC(C)N
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)NC(C)C)cc2)=C(C)C1=O
Yield: 20.7 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (200 mg, 0.58 mmol) obtained in Example 1 and isopropylamine (44 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (46 mg, 0.12 mmol, yield 21%).
Reaction SMILES: C1(C2N3C=CN=C(N)C3=C(I)[N:6]=2)CCC1.[CH3:16][O:17][C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26]2[N:30]3[CH:31]=[CH:32][N:33]=[C:34](Cl)[C:29]3=[C:28]([I:36])[N:27]=2)[CH2:22][CH2:21]1)=[O:19]>>[CH3:16][O:17][C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26]2[N:30]3[CH:31]=[CH:32][N:33]=[C:34]([NH2:6])[C:29]3=[C:28]([I:36])[N:27]=2)[CH2:22][CH2:21]1)=[O:19]
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(Cl)nccn32)CC1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Product: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(N)nccn32)CC1

Procedure:
Prepared according to the procedure described above for 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine, except using trans-4-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclohexanecarboxylic acid methyl ester. 1H NMR (d6-DMSO): δ 7.65 (d, J=4.8 Hz, 1H), 6.96 (d, J=4.8 Hz, 1H), 6.52 (br s, 2H), 3.65 (s, 3H), 3.16 (m, 1H), 2.71 (m, 1H), 2.15-2.00 (m, 2H), 1.80-1.60 (m, 6H) MS (ES+): m/z 400.98 (100) [M+1].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[O:13])OC(=O)[NH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21].C(Cl)Cl>C1(C)C=CC=CC=1>[NH2:9][C:8]1[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[C:12]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[O:17][CH3:16])=[O:13]
Reactant: COc1ccccc1CN
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)o1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccccc1CNC(=O)c1ccc([N+](=O)[O-])cc1N
Reaction time: 0.5 h

Procedure:
A mixture of 9.3 g 7-nitro-1H-benzo[d][1.3]oxazine-2,4-dione (45 mmol) and 12.3 g 2-methoxybenzylamine (90 mmol) in 200 mL toluene was stirred for 30 minutes at reflux, then mixed with methylene chloride and washed repeated with water. The organic phase was dried, concentrated and the solid residue was dried and reacted further without further purification.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)([CH3:12])[CH3:11].[Br:26][C:27]1[N:32]2[CH:33]=[CH:34][N:35]=[C:31]2[C:30](Br)=[N:29][CH:28]=1>CC(O)C>[Br:26][C:27]1[N:32]2[CH:33]=[CH:34][N:35]=[C:31]2[C:30]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([CH:16]3[CH2:15][CH2:14][N:13]([CH:10]([CH3:12])[CH3:11])[CH2:18][CH2:17]3)=[CH:24][CH:23]=2)=[N:29][CH:28]=1
Reactant: CC(C)N1CCC(c2ccc(N)cc2)CC1
Reactant: Brc1ncc(Br)n2ccnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1

Procedure:
N,N-Diisopropylethylamine (360 μL, 2.2 mmol) is added to a mixture of 4-(1-isopropylpiperidin-4-yl)phenylamine (220 mg, 1.0 mmol) and 5,8-dibromoimidazo[1,2-a]pyrazine (280 mg, 1.0 mmol) in iPrOH (5 mL) and heated at reflux for 48 h. The mixture is cooled and the solvent evaporated under reduced pressure to afford an orange-brown solid. This is partitioned between DCM (50 mL) and water (20 mL) and the layers are separated. The organic phase is washed with citric acid (10% aq., 3×25 mL). The combined washings are extracted with DCM (25 mL) and then made basic by addition of NaHCO3 (s). The mixture is extracted with DCM (3×25 mL) and the combined extracts dried over MgSO4 and evaporated. The material is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:20]([C:17]1[NH:18][N:19]=[C:15]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:23])[CH:16]=1)=[O:22])[CH3:25]
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)[nH]n1
Reactant: CCN
Product: CCNC(=O)c1cc(NCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Yield: 41 %

Procedure:
As described for example 152, 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2H-pyrazole-3-carboxylic acid was converted, using ethylamine instead of 2-hydroxy-2-methypropylamine, to the title compound (14 mg, 41%) which was obtained as an off white solid. MS: m/e=344.2 [M+H]+.