Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)Cl.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:48]1[CH:49]=[CH:50][CH:51]=[C:52]2[C:57]=1[N:56]=[C:55]([C:58]1[N:62]3[CH:63]=[C:64]([C@@H:67]([N:72]4[CH2:76][CH2:75][C@H:74]([NH:77][C:78](=[O:84])[O:79][C:80]([CH3:83])([CH3:82])[CH3:81])[CH2:73]4)[C:68]([F:71])([F:70])[F:69])[CH:65]=[CH:66][C:61]3=[N:60][N:59]=1)[CH:54]=[CH:53]2.[CH2:85]([SH:87])[CH3:86].C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH2:85]([S:87][C:48]1[CH:49]=[CH:50][CH:51]=[C:52]2[C:57]=1[N:56]=[C:55]([C:58]1[N:62]3[CH:63]=[C:64]([C@@H:67]([N:72]4[CH2:76][CH2:75][C@H:74]([NH:77][C:78](=[O:84])[O:79][C:80]([CH3:83])([CH3:82])[CH3:81])[CH2:73]4)[C:68]([F:71])([F:70])[F:69])[CH:65]=[CH:66][C:61]3=[N:60][N:59]=1)[CH:54]=[CH:53]2)[CH3:86]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cccc(Br)c5n4)n3c2)C(F)(F)F)C1
Reactant: CCS
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCSc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Yield: 62 %

Procedure:
CHCl3 (8.75 mg, 0.00845 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (9.78 mg, 0.0169 mmol), tert-butyl (S)-1-((R)-1-(3-(8-bromo quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (100 mg, 0.169 mmol), ethanethiol (31.5 mg, 0.507 mmol) and N-ethyl-N-isopropylpropan-2-amine (131 mg, 1.01 mmol) in dioxane were heated to 150° C. under microwave irradiation for 1 hour. After cooling, the reaction was concentrated under reduced pressure and purified by chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 30 column volumes) to yield tert-butyl (S)-1-((R)-1-(3-(8-(ethylthio)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (60 mg, 62.0% yield)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([NH:17]C(C)(C)C)=[S:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:22].C(OCC)C>C(O)(=O)C>[BrH:22].[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([NH2:17])=[S:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=S)NC1CCN(Cc2ccccc2)CC1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: NC(=S)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
17 g of N-(1-benzylpiperid-4-yl)-N'-tert-butylthiourea are added to 170 ml of 33% hydrobromic acid in acetic acid; the reaction mixture is stirred at room temperature for 4 hours, then it is poured over diethylether. The crystals obtained are filtered and they are thoroughly washed with diethylether in order to obtain white crystals which melt at 120° C.; yield: quantitative.
Reaction SMILES: Cl[C:2]1(Cl)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][C:3]1=[O:11].C(O)(=O)C.O>CCOCC.[Zn]>[CH2:4]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:2][C:3]1=[O:11]
Reactant: O=C1CC2(CCOCC2)C1(Cl)Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC2(CCOCC2)C1
Reaction time: 24 h

Procedure:
The impure 1,1-dichloro-7-oxaspiro[3.5]nonan-2-one from Step B was stirred with zinc (150 mg; 2.30 mmol) and 5 mL of acetic acid/water (1:1) for 4 hours. The mixture was stored at −20° C. for 1 day, diluted with ether (20 mL) and filtered through a pad of Celite®. The solution was neutralized with aqueous sodium bicarbonate solution and extracted into ether (5×20 mL). The combined ether extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure. The material was purified by chromatography on silica gel, eluting with 1:1 ethyl acetate/hexane to give the product as a colorless oil (61 mg).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:21](O)([CH3:24])([CH3:23])[CH3:22].C1CCN2C(=NCCC2)CC1.Cl>CN(C=O)C.O>[S:1]1[CH:5]=[C:4]([C:6]([O:8][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:7])[N:3]=[CH:2]1
Reactant: CC(C)(C)O
Reactant: O=C(O)c1cscn1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)(C)OC(=O)c1cscn1
Temperature: 60 °C
Yield: 47 %

Procedure:
To a solution of thiazole-4-carboxylic acid 7.1 (1 g, 7.2 mmol) and carbonyldiimidazole (6.3 g, 38.7 mmol) in commercial dry DMF (50 mL) under N2 was stirred at 50° C. for 20 min. Tert-butanol (8.6 g, 116.0 mmol) and DBU (5.8 mL, 38.7 mmol) were then successively added at once and the reaction was warmed at 60° C. for 48 h. The RM was then allowed to cool down to RT and the pH was adjusted to 4 with a solution of HCl (2M, ˜80 mL). The mixture was diluted with water (250 mL) and extracted with Et2O (3×100 mL). The combined org. layers were washed with brine (250 mL), dried over MgSO4, concentrated and purified on silica gel using DCM to afford title product as yellowish oil (47%). Yield: 3.37 g (47%). LCMS: P=98%, rt=3.65 nm, m/z=186.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])(=[O:3])[CH3:2].Cl.N([O-])=O.[Na+].[N-:16]=[N+:17]=[N-].[Na+]>O.CCOCC.CCCCCC>[C:1]([C:4]1[CH:5]=[C:6]([N:7]=[N+:16]=[N-:17])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1cccc(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(=O)c1cccc(N=[N+]=[N-])c1
Reaction time: 0.33 h

Procedure:
A mixture of 10.8g. (0.08 mole) of 3-acetylaniline in 50 ml. of water was treated with 20 ml. of concentrated HCl and cooled to 0° C. There was then added a solution of 6.07g. (0.088 mole) of NaNO2 in 20 ml. of water. The reaction mixture was aged for 20 minutes, and there was then added 25 ml. of hexane and 25 ml. of ether, followed by a solution fo 5.72g. (0.088 mole) of NaN3 in 20 ml. of water. The reaction mixture was aged for 1/2 hour at room temperature, after which the aqueous and organic components were separated, and the aqueous component extracted with 50 ml. of ether. The organic component and extract were dried over MgSO4 and concentrated under reduced pressure to 12.72g. (99%) of product whose structure as 3-acetylphenylazide was confirmed by IR.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH:11]1[CH2:23][OH:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:25]I>CN(C=O)C.CCOCC>[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH:11]1[CH2:23][O:24][CH3:25])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
Sodium hydride (0.857 g, 21.42 mmol) was added portionwise to stirred Et2O (23.0 ml) at 25° C. under nitrogen. A solution of (1,4-dibenzylpiperazin-2-yl)methanol (1.411 g, 4.76 mmol) in DMF (8.0 ml) was added portionwise under nitrogen. The resulting suspension was stirred at room temperature for 1 h. A solution of methyl iodide (0.454 ml, 7.28 mmol) in Et2O (7.0 ml) was added dropwise to the reaction mixture at 10° C., under nitrogen. The resulting mixture was stirred at room temperature for 21 h. The reaction mixture was quenched with water (35 mL and extracted with Et2O (3×50 mL). The organic layers were combined and washed with water (50 mL), dried over MgSO4, filtered and evaporated to afford 1,4-dibenzyl-2-(methoxymethyl)piperazine (1.580 g, 107%) as a yellow oil. This was used directly without further purification.
Reaction SMILES: FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O.[CH3:22][C:23]([CH3:37])([O:25][C:26]([NH:28][C@H:29]([C:34]([OH:36])=[O:35])[CH2:30]C(=O)N)=[O:27])[CH3:24].[N:38]1C=CC=CC=1.C(=O)([O-])O.[Na+].[CH:49]1[C:61]2[CH:60]([CH2:62][O:63][C:64](ON3C(=O)CCC3=O)=[O:65])[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]=2[CH:52]=[CH:51][CH:50]=1>CN(C)C=O.O>[CH3:37][C:23]([CH3:22])([O:25][C:26]([NH:28][C@H:29]([C:34]([OH:36])=[O:35])[CH2:30][NH:38][C:64]([O:63][CH2:62][CH:60]1[C:61]2[CH:49]=[CH:50][CH:51]=[CH:52][C:53]=2[C:54]2[C:59]1=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:65])=[O:27])[CH3:24]
Reactant: c1ccncc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Bis(trifluoroacetoxy)iodobenzene (44.4 g, 103.2 mmol) was added to a solution of N-[(1,1-dimethylethoxy)carbonyl]-L-asparagine (Boc-Asn; 20.00 g, 86.1 mmol) in N,N-dimethylformamide/water (2:1; 300 mL). The solution was stirred at room temperature for 30 min and then pyridine (10 mL, 123.6 mmol) was added. The solution was stirred at room temperature for 4.5 h and then the solvent was evaporated (45° C., ˜0.5 mm Hg). The residue was dissolved in acetone/water (1:1; 400 mL) and sodium hydrogen carbonate (31.8 g, 378.5 mmol) and 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-2,5-pyrrolidinedione (Fmoc-OSu; 34.74 g, 103.0 mmol) were added. The mixture was stirred at room temperature overnight, then the acetone was evaporated and the mixture was acidified to pH 1 with 1 M HCl and extracted with ethyl acetate (200 mL, then 100 mL). The combined organic layers were washed with brine (3×50 mL), dried (Na2SO4), filtered, evaporated (45° C., ˜0.5 mm Hg), and chromatographed (50-60% ethyl acetate/hexanes) to give N-[(1,1-dimethylethoxy)carbonyl]-3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine (32.33 g, 88%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[F:29][C:30]1([F:35])[CH2:34][CH2:33][NH:32][CH2:31]1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[F:29][C:30]1([F:35])[CH2:34][CH2:33][N:32]([C:2]2[C:21]([C:22]3[CH:27]=[N:26][CH:25]=[N:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:17])([F:19])[F:18])=[CH:11][CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:31]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncnc2)c1
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(F)(F)C2)c(-c2cncnc2)c1
Temperature: 140 °C
Reaction time: 23 h

Procedure:
6-Chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 223.1, 100 mg, 0.253 mmol) was suspended in iPrOH (0.5 mL). 3,3-Difluoropyrrolidine hydrochloride (72.7 mg, 0.507 mmol) and DIPEA (0.177 mL, 1.013 mmol) were added at RT. The light brown solution was stirred at 140° C. for 23 h. The RM was diluted with EtOAc (50 mL) and washed with a 2 N citric acid solution (20 mL) and water (3×20 mL). The combined aq. phases were extracted with EtOAc and the combined extracts were dried over Na2SO4, filtered, and the solvent was evaporated off under reduced pressure to give the crude material that was purified by flash chromatography (RediSep® Silica gel column, 24 g, DCM/EtOAc 7:3). The resulting product was dissolved in MeOH (2 mL). The resulting white suspension was stirred at RT for 15 min then filtered. The solid was washed with MeOH (5 mL) and dried to afford the title product as a white solid. HPLC (Condition 10) tR=7.017 min, UPLC-MS (Condition 3) tR=1.09 min, m/z=466.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.39 (spt, J=7.04 Hz, 2H) 3.37 (t, J=7.23 Hz, 2H) 3.62 (t, J=13.10 Hz, 2H) 7.37 (d, J=8.99 Hz, 2H) 7.82-7.89 (m, 2H) 8.15-8.19 (m, 1H) 8.82-8.85 (m, 1H) 8.94 (d, J=0.78 Hz, 2H) 9.23 (s, 1H) 10.27 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][OH:4].CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[C:18]=1[O:24][CH3:25]>C(OCC)(=O)C>[CH3:25][O:24][C:18]1[C:19]([CH3:23])=[N:20][CH:21]=[CH:22][C:17]=1[O:4][CH2:3][C:2]([F:9])([F:1])[C:5]([F:8])([F:7])[F:6]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: COc1c(Cl)ccnc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1c(OCC(F)(F)C(F)(F)F)ccnc1C

Procedure:
To 2,2,3,3,3-pentafluoropropanol (21 ml) were added in small portions, potassium tert-butoxide (23.6 g) and then 4-chloro-3-methoxy-2-methyl-pyridine (7.5 g). After being refluxed for 40 hours, the reaction mixture was cooled, to which ethyl acetate was added and the insoluble substance was filtered off. The filtrate was concentrated and purified by column chromatography, to give 3-methoxy-2-methyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine (1.7 g) as a light yellow oil while 4.1 g of the starting material was recovered at the same time.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][C:11]=2[N:12]=1.[Cl:19]CC1C=CC2OC(C3C=CC=C(F)C=3)=NC=2C=1>>[Cl:19][CH2:17][C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:12][C:11]=2[CH:13]=1
Reactant: OCc1ccc2oc(-c3ccccc3F)nc2c1
Reactant: Fc1cccc(-c2nc3cc(CCl)ccc3o2)c1
Product: Fc1ccccc1-c1nc2cc(CCl)ccc2o1

Procedure:
Compound 75B was reacted in a manner analogous to Compound 69C to give the title product. MS m/z 262 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[C:12]=2[C:13](=[O:22])[C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37]Cl)[CH3:34]>CC(C)=O>[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[C:12]=2[C:13](=[O:22])[C:14]2[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[CH:6][CH:7]=1)[CH3:34]
Reactant: Cc1cc(C)cc(C(=O)c2c(-c3ccc(O)cc3)oc3ccccc23)c1
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)CCOc1ccc(-c2oc3ccccc3c2C(=O)c2cc(C)cc(C)c2)cc1

Procedure:
2-p-Hydroxyphenyl-3-(3',5'-dimethylbenzoyl)benzofuran (5.25 g., 15.3 mmol.) was dissolved in 200 ml. of dry acetone and 10.5 g. (0.076 mol.) of potassium carbonate and 2.10 g. (15.3 mmol.) of 2-diethylaminoethyl chloride were added. The reaction mixture was refluxed for three hours, then it was cooled and filtered. The filtrate was concentrated at reduced pressure to give the title compound as an oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].I[C:14]1[C:19]([CH3:20])=[CH:18][C:17](Br)=[CH:16][C:15]=1[CH3:22]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([C:12]#[C:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=3)=[CH:16][C:15]=2[CH3:22])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#Cc1ccc(CCCC)cc1
Reactant: Cc1cc(Br)cc(C)c1I
Product: CCCCc1ccc(C#Cc2cc(C)c(C#Cc3ccc(CCCC)cc3)c(C)c2)cc1

Procedure:
1,4-bis(4-n-Butylphenylethynyl)-2,6-dimethylbenzene is prepared from 4-n-butylphenylacetylene and 1-iodo-4-bromo-2,6-dimethylbenzene analogously to the synthesis described under 1A.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7]([CH:9]([NH:11][C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH:22]4[CH2:26][NH:27]C(OC(C)(C)C)=O)=[O:20])=[C:15]([Cl:35])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7]([CH:9]([NH:11][C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH:22]4[CH2:26][NH2:27])=[O:20])=[C:15]([Cl:35])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(NC(=O)c1ccc(C(=O)N2CCCC2CNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.25 g (0.446 mmol) of N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-chloro-4-[2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]benzamide (Example 9) is dissolved in 10 mL of dichloromethane and after the addition of 0.68 mL (8.9 mmol) of trifluoroacetic acid stirred for 1 hour at ambient temperature. After elimination of the volatile constituents in vacuo, the residue is taken up in ethyl acetate, the solution washed twice with 2 molar sodium hydroxide solution and three times with demineralized water, and dried over sodium sulfate. Finally, the solvent is eliminated in vacuo. Yield: 120 mg (58%; mixture of all four stereoisomers); Rf value: 0.10 (silica gel; dichloromethane/ethanol=9:1); C22H23Cl2N5O2 (460.36); mass spectrum: (M+H)+=460/462/464 (chlorine isotope).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[C:22]3[CH2:30][CH2:29][NH:28][CH2:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH:11]=1.Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>C(O)C>[CH:33]1([CH2:32][N:28]2[CH2:29][CH2:30][C:22]3[C:21]([NH:20][C:12]4[CH:11]=[N:10][C:19]5[C:14]([CH:13]=4)=[CH:15][CH:16]=[CH:17][CH:18]=5)=[N:26][CH:25]=[N:24][C:23]=3[CH2:27]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: c1ccc2ncc(Nc3ncnc4c3CCNC4)cc2c1
Reactant: BrCC1CCCCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2ncc(Nc3ncnc4c3CCN(CC3CCCCC3)C4)cc2c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 9.4 %

Procedure:
Diisopropylethyl amine(258 mg, 2 mmol) was added to the solution of 5,6,7,8-tetrahydro-N-(quinolin-3-yl)pyrido[3,4-d]pyrimidin-4-amine (55 mg, 0.2 mmol) and (bromomethyl)cyclohexane (177 mg, 1 mmol) in ethanol (2 ML) and stirred at 80° C. for 48 h. Solvent was removed in vacuo, and the residue was purified by column chromatography to yield the product as a light orange powder (7 mg, 9.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(N(CC)C(C)C)(C)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl.[O:45]1[CH:49]=[CH:48][C:47]([NH2:50])=[N:46]1.C(=O)([O-])O.[Na+]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:34]([NH:50][C:47]2[CH:48]=[CH:49][O:45][N:46]=2)=[O:36])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: Nc1ccon1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Clc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccon4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.5 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (20 mg) was dissolved in chlorobenzene (2 ml) and N,N-diisopropylethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (18 mg) in chlorobenzene (0.5 ml) was then added to the solution, and the mixture was stirred at room temperature for 30 min. Next, 3-isoxazolamine (10 mg) was added thereto, and the mixture was further stirred at 110° C. overnight. The reaction solution was developed through diatomaceous earth impregnated with a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with chloroform. The solvent in the extract was removed by distillation. The residue was purified by HPLC using chloroform/methanol for development to give the title compound (2 mg, yield 8%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C=[N+]=[N-])(C)C.CCOCC.[BH4-].[Na+]>CO.C(O)(=O)C>[OH:19][CH2:18][C:17]1[CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[N:23]=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(=O)O)cc(C(F)(F)F)n2)CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(CO)cc(C(F)(F)F)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]oxy}-6-(trifluoromethyl)isonicotinic acid (1.4 g, 3.6 mmol, prepared by the method of Step 2) in methanol (70. mL) at 0° C. was added 2.0 M trimethylsilyldiazomethane in ether (18 mL, 36 mmol) dropwise until TLC indicated complete reaction. Excess reagent was discharged by dropwise addition of acetic acid to the mixture cooled in an ice bath. Solvent was removed by rotary evaporation. The residue was dissolved in ethanol (28 mL), cooled to 0° C., and sodium tetrahydroborate (0.26 g, 7.0 mmol) was added. The cooling was discontinued and the reaction was allowed to stir at room temperature for 30 minutes. It was re-cooled in an ice bath and an additional portion of Sodium tetrahydroborate (0.27 g, 7.2 mmol) was added. The reaction mixture was allowed to reach room temperature and stir until the reaction was complete as determined by analytical LCMS and TLC. The reaction was quenched by the addition of saturated ammonium chloride, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, using a 120 g silica gel cartridge and eluting with a gradient from 0-30% EtOAc in hexanes afforded product as a colorless oil (0.90 g, 67%). 1H NMR (400 MHz, CDCl3) δ 7.22 (s, 1H), 6.90 (s, 1H), 5.27 (tt, J=7.7, 3.7 Hz, 1H), 4.74 (d, J=2.5 Hz, 2H), 3.81-3.63 (m, 2H), 3.31 (ddd, J=13.4, 8.4, 3.7 Hz, 2H), 1.98 (ddt, J=13.5, 7.0, 3.8 Hz, 2H), 1.72 (dtd, J=12.5, 8.2, 4.0 Hz, 2H), 1.47 (s, 9H). 19F NMR (376 MHz, CDCl3) δ −69.21 (s). LCMS (M-tBu+H)+: 321.1.
Reaction SMILES: CO[C:3]([C:5]1[CH:22]=[C:21]2[C:8]([S:9](=[O:24])(=[O:23])[NH:10][C:11]3[C:20]2=[CH:19][CH:18]=[C:17]2[C:12]=3[N:13]=[CH:14][CH:15]=[CH:16]2)=[CH:7][CH:6]=1)=[O:4].[CH3:25][NH2:26]>>[CH3:25][NH:26][C:3]([C:5]1[CH:22]=[C:21]2[C:8]([S:9](=[O:23])(=[O:24])[NH:10][C:11]3[C:20]2=[CH:19][CH:18]=[C:17]2[C:12]=3[N:13]=[CH:14][CH:15]=[CH:16]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CN
Reactant: COC(=O)c1ccc2c(c1)-c1ccc3cccnc3c1NS2(=O)=O
Product: CNC(=O)c1ccc2c(c1)-c1ccc3cccnc3c1NS2(=O)=O
Yield: 81.3 %

Procedure:
In a similar fashion using route 53 general procedure 122,6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid methyl ester 307 (20 mg, 0.058 mmol), methylamine (33% in EtOH; 4 ml, 0.58 mmol) at 100° C. gave the title compound (16 mg 84%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:9][C:8]2[CH:10]=[C:11]([NH:14][C:15]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:21][CH:22]=3)=[O:16])[CH:12]=[CH:13][C:7]=2[N:6]=1)=[O:4].[Li+].[OH-]>CO.O.O1CCCC1>[C:23]1([C:20]2[N:19]=[CH:18][C:17]([C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:7]4[N:6]=[C:5]([C:3]([OH:4])=[O:2])[NH:9][C:8]=4[CH:10]=3)=[O:16])=[CH:22][N:21]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1nc2ccc(NC(=O)c3cnc(-c4ccccc4)nc3)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc2nc(C(=O)O)[nH]c2c1)c1cnc(-c2ccccc2)nc1
Yield: 72.7 %

Procedure:
A solution of 6-[(2-phenyl-pyrimidin-5-carbonyl)-amino]-1H-benzoimidazole-2-carboxylic acid methyl ester (0.44 mmol) and LiOH (4.40 mmol) in MeOH/water/tetrahydrofuran (1:1:1, 60 mL) is stirred at room temperature overnight. MeOH and THF are evaporated in vacuo and the aqueous mixture is acidified with 5% HCl to pH ˜2. The resulting precipitate is filtered, washed with water (10 mL) and dried to give 6-[(2-phenyl-pyrimidin-5-carbonyl)-amino]-1H-benzoimidazole-2-carboxylic acid as a solid (115 mg). MS: 360 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 7.52-7.70 (m, 5H), 8.30 (s, H), 8.48 (m, 3H), 9.28 (S, H), 9.38 (s, 2H), 10.73 (s, N—H).