Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C@H:12]([N:14]([CH3:34])[C:15]([N:17]2[CH2:22][CH2:21][N:20]3[C:23](=[O:26])[CH2:24][CH2:25][C@H:19]3[C@@H:18]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:45](Cl)(=[O:48])[O:46][CH3:47]>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:2]1[CH:3]=[C:4]([C@H:12]([N:14]([CH3:34])[C:15]([N:17]2[CH2:22][CH2:21][N:20]3[C:23](=[O:26])[C:24]([C:45]([O:46][CH3:47])=[O:48])([C:45]([O:46][CH3:47])=[O:48])[CH2:25][C@H:19]3[C@@H:18]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: COC(=O)Cl
Reactant: Cc1ccccc1[C@H]1[C@@H]2CCC(=O)N2CCN1C(=O)N(C)[C@H](C)c1cc(Cl)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)OC)C[C@H]2[C@H](c3ccccc3C)N(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCN2C1=O
Reaction time: 0.5 h
Yield: 112.1 %

Procedure:
To a solution of (1S,8aS)-N-((R)-1-(3-chloro-5-(trifluoromethyl)phenyl)ethyl)-N-methyl-6-oxo-1-o-tolylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide (300 mg, 0.61 mmol) in anhydrous THF (20 mL) under N2 atmosphere was added LiHMDS (2.3 mL, 1 M in THF, 2.3 mmol) at −60° C. The reaction was stirred for 30 min followed by addition of methyl carbonochloridate (134 mg, 1.43 mmol). After stirring for another 3 h at room temperature, the reaction was quenched with water at 0° C. and then extracted with EtOAc (2×30 mL). The combined organic layers were dried over anhydrous Na2SO4 and then concentrated in high vacuum. The residue was purified by silica gel chromatography (DCM/MeOH=20/1 to 10/1) to give the title compound (220 mg, yield: 59%); m/z (ES+): 610 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([CH3:22])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:22])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1N
Yield: 90.7 %

Procedure:
The 3-(3-Methyl-4-nitro-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (12.0 g, 43 mmol) was dissolved in 50 mL methanol and 50 mL ethyl acetate. An amount of 1.0 g of 10% wet Pd—C (50% w/w) was added. The reaction mixture was subjected to hydrogenation under 40 PSI of hydrogen for 3 hours. The solution was then filtered through Celite to remove catalyst. The filtrate was concentrated under reduced pressure to give the desired product (10.8 g, 39 mmol). 1H-NMR (400 MHz, CDCl3): δ=6.60 (m, 1H), 6.02 (m, 1H), 5.95 (m, 1H), 4.78 (m, 1H), 4.24 (m, 2H), 3.95 (m, 2H), 3.45 (br, 1H), 2.15 (s, 3H), 1.45 (s, 9H). MS: 301 (M++23).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:21][CH2:22][CH2:23][CH2:24][N:25]1[C:30](=[O:31])[CH2:29][N:28]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:27][C:26]1=[O:39]>>[ClH:21].[ClH:21].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][N:25]3[C:30](=[O:31])[CH2:29][N:28]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[CH2:27][C:26]3=[O:39])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: O=C1CN(Cc2ccccn2)CC(=O)N1CCCCl
Product: Cl
Product: O=C1CN(Cc2ccccn2)CC(=O)N1CCCN1CCC(=C(c2ccccc2)c2ccc(F)cc2)CC1

Procedure:
This compound was prepared from 4-[(4-fluorophenyl)phenylmethylene]piperidine and 1-(3-chloropropyl)-4-(2-pyridylmethyl)-2,6-piperazinedione according to the process described in Example 6, Stage E.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]([O:11][CH3:12])=[O:10].[CH3:14][O:15][NH3+:16].[Cl-].O>CO>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:16][O:15][CH3:14])[C:9]([O:11][CH3:12])=[O:10]
Reactant: CO[NH3+]
Reactant: COC(=O)C(=O)c1ccccc1O
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CON=C(C(=O)OC)c1ccccc1O

Procedure:
10.4 g (0.0533 mol) of methyl 2-hydroxyphenylglyoxylate (HPLC: 92.4%, log p=1.87) from process step 2 and 7.4 g (0.089 mol) of 0-methylhydroxylamine hydrochloride in 150 ml of methanol are boiled under reflux for three hours. The reaction mixture is poured into water, the product is extracted with diethyl ether, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. This gives 8.2 g of crude product which, according to HPLC, contains 17.2% methyl E-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=1.48 and 65.4% methyl Z-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=2.38.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([OH:27])[C:17]3=[C:18]([F:26])[CH:19]=[N:20][C:21]4[CH:22]=[CH:23][C:24](=[O:25])[N:15]([C:16]=43)[CH2:14]2)(=O)=O)=CC=1.[O:28]1[C:37]2[CH:36]=[C:35]([CH2:38][N:39]([CH:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[N:34]=[CH:33][C:32]=2[O:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:28]1[C:37]2[CH:36]=[C:35]([CH2:38][N:39]([CH:47]3[CH2:52][CH2:51][N:50]([CH2:12][C:13]4([OH:27])[C:17]5=[C:18]([F:26])[CH:19]=[N:20][C:21]6[CH:22]=[CH:23][C:24](=[O:25])[N:15]([C:16]=65)[CH2:14]4)[CH2:49][CH2:48]3)[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[N:34]=[CH:33][C:32]=2[O:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2(O)Cn3c(=O)ccc4ncc(F)c2c43)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CC2(O)Cn3c(=O)ccc4ncc(F)c2c43)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [(4R/S)-3-fluoro-4-hydroxy-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl]methyl 4-methylbenzenesulfonate (100 mg, 0.25 mmol), 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (84 mg, 0.24 mmol) (for a synthesis, see WO2004058144, Example 99(h)), sodium carbonate (77 mg, 0.7 mmol) and ethanol (2.5 ml) was stirred at room temperature overnight then evaporated under vacuum. The residue was treated with water and the mixture extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulphate and evaporated under vacuum. The residue was chromatographed on silica eluting with 0-100% ethyl acetate in dichloromethane then 0-10% methanol in ethyl acetate affording a yellow oil (88 mg, 64%).
Reaction SMILES: Br[CH:2]1[CH2:4][C:3]1([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CC(C)([O-])C.[K+].C(OCC)C.O>CS(C)=O>[CH3:11][C:3]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:4]=[CH:2]1
Reactant: CC1(c2ccccc2)CC1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: CC1(c2ccccc2)C=C1
Temperature: 72 °C
Yield: 91.5 %

Procedure:
To a solution of 1.56 g (0.00739 mol) of 2-bromo-1-methyl-1-phenylcyclopropane in 5 ml of dimethylsulfoxide was added 1.429 g (0.0127 mol) of potassium tert-butoxide. After the reaction was heated to 72° C. for 4 hours, diethyl ether and water were added. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo to yield 0.88 g of 70% pure 3-methyl-3-phenylcyclopropene as an oil. The major byproduct (roughly 20%) was 1-methyl-1-phenylcyclopropane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([OH:19])=O)[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:68][CH2:69][CH2:70][CH2:71][N:72]1[CH2:76][CH2:75][CH2:74][CH2:73]1>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:68][CH2:69][CH2:70][CH2:71][N:72]3[CH2:76][CH2:75][CH2:74][CH2:73]3)=[O:19])[CH:13]=2)[CH:7]=1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Reactant: NCCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN5CCCC5)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (200 mg, 0.43 mmol) in 10 ml of anhydrous DMF were added HATU (198 mg, 0.52 mmol) and N,N-diisopropylethylamine (166 mg, 1.3 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of N-(3-aminopropyl)pyrrolidine (110 mg, 0.86 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude which was purified by silica gel chromatography eluting with 10-20% of methanol in chloroform to give 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-pyrrolidin-1-ylpropyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 160 mg, 65%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.[C:11](O)(=O)[CH2:12][C:13](O)=O.O.[Cl-:19].[Cl-:20].[Cl-].[P+3]=O>>[Cl:19][C:13]1[CH:12]=[C:11]([Cl:20])[C:8]2[C:6](=[C:5]([CH3:10])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=2)[N:7]=1
Reactant: [Cl-]
Reactant: COc1ccc(N)c(C)c1
Reactant: O=C(O)CC(=O)O
Agent: O=[P+3]
Solvent: O
Product: COc1cc(C)c2nc(Cl)cc(Cl)c2c1
Yield: 43 %

Procedure:
A mixture of 4-methoxy-2-methyl aniline 215f (5 g, 36.45 mmol), malonic acid (5.68 g, 54.67 mmol) in phosphorus oxide trichloride (36 mL) was refluxed for 16 hrs. The reaction mixture was then poured dropwise into cooled water (400 mL), extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by chromatography on silica gel (DCM) to yield compound 220f as a beige solid in 43% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.72 (s, 3H), 3.95 (s, 3H), 7.27-7.28 (m, 2H), 7.47 (s, 1H).
Reaction SMILES: BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CCCP(=O)O)=CC=3OC)N=2)=CC=1.[Br:38][C:39]1[N:44]=[C:43]([C:45](=[O:48])[NH:46][CH3:47])[C:42]([NH:49][C:50]2[C:55]([C:56]([F:59])([F:58])[F:57])=[CH:54][N:53]=[C:52]([NH:60][C:61]3[CH:75]=[CH:74][C:64]([CH2:65][CH2:66][CH:67]([PH:69](=[O:73])[O:70]CC)[CH3:68])=[CH:63][C:62]=3[O:76][CH3:77])[N:51]=2)=[CH:41][CH:40]=1>>[Br:38][C:39]1[N:44]=[C:43]([C:45](=[O:48])[NH:46][CH3:47])[C:42]([NH:49][C:50]2[C:55]([C:56]([F:59])([F:57])[F:58])=[CH:54][N:53]=[C:52]([NH:60][C:61]3[CH:75]=[CH:74][C:64]([CH2:65][CH2:66][CH:67]([PH:69](=[O:70])[OH:73])[CH3:68])=[CH:63][C:62]=3[O:76][CH3:77])[N:51]=2)=[CH:41][CH:40]=1
Reactant: CCO[PH](=O)C(C)CCc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Agent: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC(C)[PH](=O)O)cc2OC)ncc1C(F)(F)F

Procedure:
Prepared analogously to Compound 67B replacing Compound 67C with ethyl (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)propan-2-ylphosphinate (Compound 68C). MS (ESI): m/z 617.43/619.41 [M+H]+. UPLC: tR=1.30 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]1([C@@H:22]([CH2:24][OH:25])[NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)(C)C>[OH:25][CH2:24][C@@H:22]([NH:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COc1cc2ncnc(N[C@H](CO)c3ccccc3)c2cc1OC
Yield: 70 %

Procedure:
A solution of 4-chloro-6,7-dimethoxyquinazoline (225 mg, 1 mmol), (S)-2-phenylglycinol (137.2 mg, 1 mmol) and triethylamine (304 mg, 3 mmol) in isopropanol (7 ml) was heated to reflux for about 8 h. Then the mixture was evaporated under vacuum to dryness and the residue purified by gradient elution chromatography on silica gel using as eluant dichloromethane/ethanol 2-6%. Thus pure title compound was obtained in 70% yield (228 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:19])[N:12]=3)[N:9]=[C:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:5]2=[N:6][CH:7]=1.Cl[C:29]([O:31][CH3:32])=[O:30]>N1C=CC=CC=1>[NH2:19][C:13]1[C:14]([NH:18][C:29](=[O:30])[O:31][CH3:32])=[C:15]([NH2:17])[N:16]=[C:11]([N:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:8]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[N:9]2)[N:12]=1
Reactant: COC(=O)Cl
Reactant: Nc1nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc(N)c1N
Solvent: c1ccncc1
Product: COC(=O)Nc1c(N)nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc1N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under argon, 1.00 g (2.72 mmol) of the compound from example 6A was initially charged in pyridine (55 ml), the mixture was cooled to 0° C. and 228 μl (2.72 mmol) of methyl chloroformate (solution in 10 ml of dichloromethane) were then added dropwise. The reaction mixture was stirred further at RT overnight and then concentrated. The residue was triturated with ethanol and the solid was filtered off and dried at 50° C. under high vacuum. This gave 873 mg (75% of theory) of the title compound as a beige solid. The filtrate was re-concentrated, and purification by preparative RP-HPLC (acetonitrile:water (+0.1% formic acid)−gradient) of the residue gave a further 180 mg (16% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:10].[Cu][C:12]#[N:13]>CN(C=O)C>[NH2:6][C:5]1[CH:7]=[C:8]([Cl:9])[C:2]([C:12]#[N:13])=[C:3]([Cl:10])[CH:4]=1
Reactant: Nc1cc(Cl)c(Br)c(Cl)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)cc(N)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared from the reaction of 4-bromo-3,5-dichloroaniline (6.88 g, 28.6 mmol) and Copper(I)cyanide (2.56 g, 28.6 mmol) in DMF (48 mL) under microwave irradiation at 190° C. for 1 h. After the completion of the reaction, the mixture was cooled to RT and quenched with 200 mL of 12% ammonia solution. The resultant mixture was stirred for 30 min at RT and the precipitate was filtered, washed with water and dried under vacuum. Yield 3.725 g. 1H NMR (400 MHz; d6-DMSO): δ 6.70 (s, 1H), 6.79 (s, 1H).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:22]1[CH2:28][CH:27]2[NH:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1)[CH2:18][CH2:19][CH2:20][CH3:21]>CC#N>[CH3:16][C@H:3]([CH2:2][N:29]1[CH:24]2[CH2:25][CH2:26][CH:27]1[CH2:28][CH:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23]2)[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15]
Reactant: CCCCCC1CC2CCC(C1)N2
Reactant: C[C@H](CI)CN1C(=O)CSc2ccccc21
Solvent: CC#N
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)CSc2ccccc21
Temperature: 40 °C
Reaction time: 120 h
Yield: 48.6 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one (108LM37-34) (0.080 g, 0.231 mmol) and 3-pentyl-8-azabicyclo[3.2.1]octane (104KS32-2) (0.050 g, 0.276 mmol) in MeCN (½ mL) were reacted according to GP10 shaking at 40° C. for 5 days. Purified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:50+1% Et3N) to give the title compound (108LM52-49) (0.045 g, 49%). 1H NMR (CDCl3) δ 7.36 (d, J=7.6 Hz, 1H), 7.32 (d, J=7.7 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 7.00 (t, J=7.6 Hz, 1H), 4.16 (d, J=7.3 Hz, CH2), 3.34 (s, CH2), 3.10-2.95 (m, 2H), 2.25-2.17 (m, 1H), 2.15-2.03 (m, 3H), 1.94-1.75 (m, 3H), 1.70-1.60 (m, 1H), 1.60-1.50 (m, 2H), 1.40-1.15 (m, 10H), 0.90-0.80 (m, 6H); 13C NMR (CDCl3) δ 166.1, 139.2, 128.7, 127.1, 124.7, 123.4, 119.1, 60.5, 59.0, 57.4, 47.5, 38.4, 36.4, 32.2, 32.1, 31.4, 29.9, 28.5, 28.4, 27.9, 27.2, 22.9, 16.7, 14.3; HPLC-MS (ammonium acetate) [M+H]+=401.3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[N+:23]([O-])=O)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:23][C:22]1[CH:21]=[CH:20][C:4]([O:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:11][CH2:12]2)=[CH:3][C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 16 h
Yield: 65.8 %

Procedure:
tert-Butyl 4-((3-methyl-4-nitrophenoxy)methyl)piperidine-1-carboxylate (5.68 g, 16.22 mmoles) was dissolved in ethyl acetate (60 ml) and methanol (40 ml). The solution was treated with 600 mg of 10% palladium on carbon (50% water w/w). The slurry was then shaken on a Parr hydrogenator and treated with a 40 psi of hydrogen gas, at room temperature. After 16 hours, the slurry was filtered through a plug of Celite, which was subsequently washed with ethyl acetate (50 ml) and methanol (50 ml). The resulting filtrate was then evaporated at reduced pressure to give 3.42 g of tert-butyl 4-((4-amino-3-methylphenoxy)methyl)piperidine-1-carboxylate as a pink solid (100% yield). The material was used in the next step without any further purification. 1H-NMR (400 MHz, DMSO-d6) d 6.34 (d, 1H), 6.32 (s, 1H), 6.23 (d, 1H), 5.84 (br s, 2H), 3.90 (s, 2H), 3.34 (m, 4H), 2.00 (m, 1H), 1.46 (m, 4H), 1.42 (s, 9H). MS (EI): 321 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[N:4][CH:3]=1.[C:14](Cl)(Cl)=[S:15]>CC(N(C)C)=O.CCOC(C)=O.O>[N:1]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[N:4][CH:3]=1)=[C:14]=[S:15]
Reactant: S=C(Cl)Cl
Reactant: N#Cc1ncc(N)c2ccccc12
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ncc(N=C=S)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
A mixture of 4-aminoisoquinoline-1-carbonitrile (500 mg, 2.95 mmol) and thiophosgene (0.34 mL, 4.44 mmol) in DMA (5 mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc/water. The two layers were separated and the aqueous layer was extracted with EtOAc (3×). The organics were combined, washed with a saturated solution of sodium bicarbonate (2×), dried over sodium sulfate, and evaporated to dryness to afford 553 mg of 4-isothiocyanatoisoquinoline-1-carbonitrile as an orange oil. 1H NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.32 (d, 1H), 8.23 (d, 1H), 8.12 (td, 1H), 8.05 (td, 1H).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C([Li])CCC.[Cl:14]C(F)(Cl)C(F)(F)Cl>C1COCC1>[Cl:14][C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1
Reactant: FC(F)(Cl)C(F)(Cl)Cl
Reactant: CC(C)n1cncn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)n1ncnc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 141 %

Procedure:
Under an atmosphere of nitrogen a solution of 1-isopropyl-1H-[1,2,4]triazole (19 mmol) in THF (50 mL) at −78° C. was treated with n-butyllithium (11.4 mL, 2.5 M, 28.5 mmol) dropwise giving a cream yellow suspension. Further n-butyllithium (3.8 mL, 2.5 M, 9.5 mmol) was added after 1 h and stirring continued for a further 1.5 h. 1,1,2-trichlorotrifluoroethane (4.57 mL, 38 mmol) was added dropwise giving a dark brown solution. The resultant reaction mixture was stirred for 15 min before being quenched by the addition of saturated aqueous NaHCO3 (20 mL) then allowed to warm to RT. The resultant mixture was extracted twice with diethyl ether, the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo to give 5-Chloro-1-isopropyl-1H-[1,2,4]triazole as a dark oil (3.9 g) which was used in the subsequent step without further purification. 1H NMR δ (ppm) (CDCl3): 7.85 (1 H, s), 4.73-4.63 (1 H, m), 1.54-1.46 (6 H, m).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(C(F)(F)F)cc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (78 mg, 85%), MS (ISP) m/z=370.5 [(M+H)+], mp 282° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:30])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([C:27](O)=[O:28])[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:31]([F:34])([F:33])[F:32])=[N:10]2)=[CH:5][CH:4]=1.Cl.[CH3:36][NH:37][O:38][CH3:39].CCN(C(C)C)C(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[CH3:39][O:38][N:37]([CH3:36])[C:27]([C:24]1([C:21]2[CH:20]=[CH:19][C:18]([N:15]3[CH2:16][CH2:17][C:12]4[C:11]([C:31]([F:34])([F:33])[F:32])=[N:10][N:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)[C:13]=4[C:14]3=[O:30])=[CH:23][CH:22]=2)[CH2:26][CH2:25]1)=[O:28]
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C(=O)O)CC4)cc2)CC3)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C(=O)N(C)OC)CC4)cc2)CC3)cc1
Reaction time: 12 h

Procedure:
1-{4-[1-(4-Methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-phenyl}cyclopropane carboxylic acid (1.12 g, 2.37 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.255 g, 2.61 mmol) were dissolved in DMF (20.0 mL) and DIEA (2.0 mL, 11.5 mmol) was added dropwise. 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.54 g, 2.8 mmol) was added and the reaction was allowed to proceed under nitrogen at rt for 12 h. The reaction was diluted with EtOAc, washed 1N HCl, brine, dried over Na2SO4, filtered and concentrated. The reaction was purified via flash chromatography (silica, 100% EtOAc, then 10% MeOH/CH2Cl2) to give the title compound. LC/MS (ESI+) 515.6 (M+H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7]1)=O)C.[BH4-].[Na+].C(O)(=O)C>C(O)C.O>[OH:3][CH2:4][CH:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7]1
Reactant: CCOC(=O)C1Sc2ccccc2NC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1Nc2ccccc2SC1CO
Temperature: 25 °C
Yield: 50.6 %

Procedure:
To a suspension of 3.0 g of 2-ethoxycarbonyl-2H-1,4-benzothiazin-3(4H)-one in ethanol (50 ml) was added portionwise 0.95 g of sodium borohydride with stirring at room temperature. After stirring for 2 hours, the mixture was diluted with water, made acidic with acetic acid, and extracted with ether. The ether layer was washed with water, dried (MgSO4), and then concentrated under reduced pressure. The residue was washed with hexane to obtain 1.25 g (50.8%) of 2-hydroxymethyl-2H-1,4-benzothiazin-3(4H)-one as crystals. Recrystallization from ethyl acetate gave prisms, m.p. 156°-157° C.