Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[F:69][C:70]1([F:118])[C:82]2[CH:81]=[C:80]([C:83]3[NH:87][C:86]([C@@H:88]4[CH2:92][CH2:91][CH2:90][N:89]4[C:93](=[O:103])[C@@H:94]([NH:98][C:99](=[O:102])[O:100][CH3:101])[CH:95]([CH3:97])[CH3:96])=[N:85][CH:84]=3)[CH:79]=[CH:78][C:77]=2[C:76]2[C:71]1=[CH:72][C:73]([C:104]1[CH:105]=[CH:106][C:107]3[N:111]=[C:110]([C@@H:112]4[CH2:116][CH2:115][CH2:114][NH:113]4)[NH:109][C:108]=3[CH:117]=1)=[CH:74][CH:75]=2>>[CH3:60][O:59][C:57](=[O:58])[NH:56][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:113]1[CH2:114][CH2:115][CH2:116][C@H:112]1[C:110]1[NH:109][C:108]2[CH:117]=[C:104]([C:73]3[CH:74]=[CH:75][C:76]4[C:77]5[C:82](=[CH:81][C:80]([C:83]6[NH:87][C:86]([C@@H:88]7[CH2:92][CH2:91][CH2:90][N:89]7[C:93](=[O:103])[C@@H:94]([NH:98][C:99]([O:100][CH3:101])=[O:102])[CH:95]([CH3:96])[CH3:97])=[N:85][CH:84]=6)=[CH:79][CH:78]=5)[C:70]([F:69])([F:118])[C:71]=4[CH:72]=3)[CH:105]=[CH:106][C:107]=2[N:111]=1)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CCCN6)[nH]c5c4)ccc2-3)[nH]1)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c5c4)ccc2-3)[nH]1)C(C)C

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-1-((S)-2-(5-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 872.50 [M+H]+. (97.5 mg, 59%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26]>C(OCC)(=O)C.C(Cl)Cl>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:26])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCOC(=O)C(Br)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccco2)SCC(N)C1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccco2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
Following the procedure described in Example 42(h), 0.30 g of t-butyl α-[6-amino-2-(2-furyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetate [obtained as described in Example 56(f)] was N-alkylated using 0.50 g of butyl 2-bromo-4-phenylbutyrate. The resulting product was subjected to silica gel column chromatography using a 1:40 by volume mixture of ethyl acetate and methylene chloride as eluent, to isolate two isomers, A and B, (ascribed to the asymmetric carbon atom, to which the phenethyl group is attached).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC([O-])(C)C.[K+].[CH3:12][O:13][C:14]([C:16]1[C:21]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])=[C:20]([F:30])[C:19](Cl)=[C:18]([C:32](=[O:34])[CH3:33])[N:17]=1)=[O:15]>C1COCC1>[CH3:12][O:13][C:14]([C:16]1[C:21]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])=[C:20]([F:30])[C:19]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])=[C:18]([C:32](=[O:34])[CH3:33])[N:17]=1)=[O:15]
Reactant: COC(=O)c1nc(C(C)=O)c(Cl)c(F)c1Nc1ccccc1F
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1nc(C(C)=O)c(ON=C(C)C)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of acetone oxime (2.20 equivalents) at room temperature is added t-BuOK (2.20 equivalents, 1.0 M solution in THF). After stirring for 30 minutes room temperature, the reaction mixture is cooled to 0° C. A solution 6-acetyl-5-chloro-4-fluoro-3-(2-fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (1.00 equivalent) in THF is added. After stirring for 1 hour at 0-5° C., the reaction mixture is quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4, concentrated in vacuo to give 6-acetyl-4-fluoro-3-(2-fluorophenylamino)-5-isopropylideneaminooxy-pyridine-2-carboxylic acid methyl ester that is used directly. A mixture of 6-acetyl-4-fluoro-3-(2-fluorophenylamino)-5-isopropylideneaminooxy-pyridine-2-carboxylic acid methyl ester in 5% aqueous MeOH is refluxed with stirring for 1 hour. The reaction mixture is diluted with EtOAc and washed with water. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by flash column chromatography to afford the desired product.
Reaction SMILES: [ClH:1].C([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)C1C=CC=CC=1.[H][H]>[Pd].CO>[ClH:1].[CH:10]12[NH:9][CH:14]([CH2:15][CH2:16]1)[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2
Reaction time: 4 h
Yield: 97.2 %

Procedure:
Palladium on carbon (10% w/w, 500 mg) was added to a solution of 8-benzyl-3-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane hydrochloride (16.5 g, 48.0 mmol, see step (h) above) in methanol (250 mL) under a nitrogen atmosphere at 25° C. The nitrogen atmosphere was exchanged for a hydrogen atmosphere (1 atm of pressure) and the reaction was stirred rapidly. After 4 h the stirring was stopped and the reaction was filtered through a pad of Celite®. The filtrate was concentrated in vacuo to afford an off-white solid (11.6 g). The solid was slurried in acetonitrile, collected and dried in vacuo to afford 10.5 g (86%) of the title compound.
Reaction SMILES: Br[C:2]1([O:8][CH:9]2[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]1.[Li]CCCC.[B:17](OCC)([O:21]CC)[O:18]CC.Cl>C1COCC1>[CH:9]1([O:8][C:2]2[CH:7]=[CH:6][C:5]([B:17]([OH:21])[OH:18])=[CH:4][CH:3]=2)[CH2:11][CH2:10]1
Reactant: CCOB(OCC)OCC
Reactant: BrC1(OC2CC2)C=CC=CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 36 %

Procedure:
To a solution of 4-bromo-4-cyclopropoxybenzene (5.0 g, 23.4 mmol, see Example 39(c)) in THF (80 mL) at −78° C. was added n-BuLi (2.5 M solution in hexane; 9.76 mL, 24.4 mmol) over 17 min. After 40 min, B(OEt)3 (5.9 mL, 34.3 mmol) was added and the reaction was warmed to room temperature and stirred at ambient temperature for 18 h. After re-cooling to 0° C., HCl (1M solution; 70 mL, aq.) was added. After 30 min the mixture was extracted with t-BuOMe (3×50 mL), the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was washed with light petrol and filtered yielding the sub-title compound (1.5 g, 34%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:25]4[N:24]([CH3:23])[CH:28]=[CH:27][CH:26]=4)[CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: Cn1cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3cccn3C)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1-methyl-2-pyrroleboronic acid pinacol ester (96.8 mg, 0.56 mmol) and K2CO3 (116 mg, 0.84 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(1-methyl-1H-pyrrol-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 7.61 (dd, 1H), 7.57 (d, 1H), 7.4 (s, 1H), 7.37 (m, 2H), 7.17 (d, 1H), 7.07 (d, 1H), 6.8 (d, 1H), 6.21 (d, 1H), 6.1 (dd, 1H), 4.76 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.7 (m, 3H), 3.57 (m, 1H), 3.2 (m, 4H), 3.03 (m, 1H), 2.42 (s, 3H).
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[NH2:31][CH2:32][CH2:33][CH2:34][CH:35]([OH:43])[CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[OH:43][CH:35]([CH2:36][N:37]1[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]1)[CH2:34][CH2:33][CH2:32][NH:31][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: NCCCC(O)CN1CCCCC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCC(O)CN3CCCCC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 5-amino-1-piperidin-1-yl-pentan-2-ol by the procedure analogous to Example 1. MS (APCl, m/z): 530 [M+H]+.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[OH:5][N:6]=[C:7]([NH2:19])[CH2:8][C:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1>ClCCl>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH2:18][C:9]=1[CH2:8][C:7]1[NH:19][S:1](=[O:2])[O:5][N:6]=1
Reactant: NC(CC1=Cc2ccccc2CC1)=NO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S1NC(CC2=Cc3ccccc3CC2)=NO1
Yield: 14.3 %

Procedure:
Thionyl chloride (2.55 ml, 0.035 mol) was added dropwise to a mixture of N'-hydroxy-(3,4-dihydro-2-naphthalenyl)ethanimidamide (6.5 g, 0.032 mol) and pyridine (5.18 ml, 0.064 mol) in dry dichloromethane (100 ml) at 0° C. Upon completion of the addition, the reaction mixture was concentrated under reduced pressure, placed in an ice bath, diluted with deionized water (50 ml), extracted with diethyl ether (3×50 ml), filtered, dried over MgSO4 and concentrated under reduced pressure to give the crude title compound as a red-brown solid. The solid was triturated with diethyl ether (3×50 ml), dissolved in boiling diethyl ether (100 ml), vacuum filtered and recrystallized from diethyl ether (75 ml) to yield 1.14 g (14.4% yield) of pure product, m.p. 118°-120.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[C:10]([NH2:21])[C:11]([NH2:20])=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=O)=[CH:25][CH:24]=1.O>N1C=CC=CC=1>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]2[NH:20][C:11]3=[N:12][C:13]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[C:8]([C:7]4[CH:6]=[CH:5][N:4]=[CH:3][C:2]=4[F:1])[N:9]=[C:10]3[N:21]=2)=[CH:25][CH:24]=1
Reactant: Nc1nc(-c2cccnc2)c(-c2ccncc2F)nc1N
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: O
Product: Fc1ccc(-c2nc3nc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)cc1
Temperature: 120 °C
Yield: 33.3 %

Procedure:
A mixture of 5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazine-2,3-diamine (Example 153, 0.100 g, 0.35 mmol) and 4-fluorobenzoyl chloride (0.074 g, 0.46 mmol) in pyridine (1 mL) was stirred and heated to 120° C. in a sealed tube for 24 hours. Water was added and the filtered solid was purified by silica gel chromatography eluting with CH2Cl2/MeOH (98:1 to 95:5) to give the title compound (0.045 g, 33%) as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[N:10][C:5]2=[C:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:27]3[C:26]([CH3:28])=[N:25][N:24]([C:29]4[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=4)[C:23]=3[C:22](=[O:37])[NH:21]2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:27]3[C:26]([CH3:28])=[N:25][N:24]([C:29]4[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=4)[C:23]=3[C:22](=[O:37])[N:21]2[C:2]2[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[N:10][C:5]3=[C:4]([CH3:12])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: Cc1cc(Cl)nc2c1nnn2C
Reactant: COc1ncccc1-n1nc(C)c2c1C(=O)NC2c1ccc(Cl)cc1
Product: COc1ncccc1-n1nc(C)c2c1C(=O)N(c1cc(C)c3nnn(C)c3n1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 102 using 5-chloro-3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridine (Step 109.4) and 4-(4-chlorophenyl)-1-(2-methoxypyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 71.4). The crude material was first purified by silica gel chromatography (40% EtOAc/Hexane) followed by preparative achiral SFC (column 4-Ethyl-pyridine, gradient 6-11% in 6 min_total 11 min). tR: 1.25 min (LC-MS 2); ESI-MS: 501 [M+H]+ (LC-MS 2); Rf=0.19 (40% EtOAc/hexane); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.04 (s, 3H) 2.66 (s, 3H) 3.92 (s, 3H) 4.10 (s, 3H) 6.74 (s, 1H) 7.14-7.26 (m, 1H) 7.36 (m, J=8.6 Hz, 2H) 7.49 (m, J=8.6 Hz, 2H) 7.96-8.05 (m, 1H) 8.14 (d, J=0.8 Hz, 1H) 8.28-8.38 (m, 1H).
Reaction SMILES: C1(C)C(S([N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15](=[O:36])[C:16]2[CH:21]=[C:20]([NH:22]C(=O)C(F)(F)F)[CH:19]=[C:18]([NH:29]C(=O)C(F)(F)F)[CH:17]=2)(=O)=O)=CC=CC=1.[OH-].[K+]>CCO>[NH2:29][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([NH2:22])[CH:19]=1)[C:15]([C:11]1[NH:10][CH:14]=[CH:13][CH:12]=1)=[O:36]
Reactant: Cc1ccccc1S(=O)(=O)n1cccc1C(=O)c1cc(NC(=O)C(F)(F)F)cc(NC(=O)C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(N)cc(C(=O)c2ccc[nH]2)c1
Temperature: 25 °C
Yield: 64.4 %

Procedure:
To a stirred EtOH (10 mL) solution of N-toluenesulfonyl-2-(3,5-di(trifluoroacetylamino)benzoyl)pyrrole (1.00 g, 1.83 mmol), was added 40% KOH solution (2 mL) and the mixture was heated at reflux until TLC analysis showed complete conversion. The resulting solution was cooled to room temperature and worked up as in Example 7. The crude product was purified by column chromatography (SiO2, CH2Cl2:MeOH) to afford the purified product 2-(3,5-diaminobenzoyl)pyrrole (237 mg, 65% yield). 1H NMR (500 MHz, CD3OD, 25° C.) δ 2.43 (s, 3H), 6.45 (m, 1H), 6.90 (m, 1H), 7.41 (d, 2H), 7.88 (m, 3H), 7.93 (d, 2H), 8.39 (t, 1H); 13C NMR (100 MHz, CD3OD, 25° C.) δ 104.8, 105.7, 109.4, 119.5, 125.2, 130.5, 139.8, 147.8, 186.0; HRMS (EI): m/z 201.0896 (100) {M}+.
Reaction SMILES: [O:1]=[C:2]1[NH:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:3]21[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH2:4]2.[H-].[Na+].I[CH3:27]>CN(C=O)C.O>[CH3:27][N:17]1[CH2:16][CH:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:3]2([CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH2:4]2)[C:2]1=[O:1]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)C(=O)NCC2c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)C2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 6-oxo-9-phenyl-2,7-diazaspiro[4.4]nonane-2-carboxylate (commercially available) (1 g, 3.16 mmol)) in DMF (50 mL) was cooled to 0° C. and treated with sodium hydride (126 mg, 3.16 mmol)). The reaction was left to stir at 0° C. for 30 minutes and iodomethane (198 uL, 3.16 mmol) was added. The reaction mixture was left to warm to room temperature. After 3 h 30 mins, the mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo to afford a yellow oil. Purification by chromatography on silica eluting with 0-10% MeOH in TBME afforded the following diastereomers:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CN(C=O)C.C(OCC)C>[F:8][C:7]1[C:2]([N:1]=[CH:12][N:13]([CH3:15])[CH3:14])=[N:3][C:4]([OH:9])=[N:5][CH:6]=1
Reactant: Nc1nc(O)ncc1F
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)C=Nc1nc(O)ncc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
To a magnetically stirred solution of 4-amino-5-fluoro-pyrimidin-2-ol* (4.00 g, 31.0 mmol) in DMF (100 mL) was added N,N-dimethylformamide dimethyl acetal (4.00 g, 34.0 mmol). The mixture was stirred at room temperature for 72 h, diluted with diethyl ether (200 mL), and filtered. The solid product was washed with heptane to give the title compound (5.23 g, 92% yield) as a white solid: mp 240-243° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.7 (bs, 1H), 8.59 (s, 1H), 7.7 (d, J=5.6 Hz, 1H), 3.18 (s, 3H), 3.06 (s, 3H); HPLC-MS (ESI) m/z 185 (M+H)+, 183 (M−H)−. *4-amino-5-fluoro-pyrimidin-2-ol can be purchased commercially.
Reaction SMILES: [CH:1]1([CH:7]=[C:8]([C:19]2[NH:29][C:22]3=[N:23][CH:24]=[C:25]([O:27][CH3:28])[CH:26]=[C:21]3[CH:20]=2)[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:7][CH:8]([C:19]2[NH:29][C:22]3=[N:23][CH:24]=[C:25]([O:27][CH3:28])[CH:26]=[C:21]3[CH:20]=2)[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cnc2[nH]c(C(=CC3CCCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: COc1cnc2[nH]c(C(CC3CCCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 50 °C
Yield: 76.5 %

Procedure:
A mixture of 2-[2-cyclohexyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.19 mmol) and 10% palladium on activated carbon (50 mg) in methanol (200 mL) was heated at 50° C. under hydrogen (50 psi) for 6 h. The mixture was cooled to room temperature, the catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-[2-cyclohexyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (60 mg, 75%) as a light yellow solid: LC/MS m/e calcd for C23H28N2O3S [M+H]+ 413.56, observed 413.3.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:24])[N:10]=[N:11][C:12]=2[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:16]=[C:15](Cl)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:25]1[CH2:28][CH2:27][CH2:26]1>>[N:25]1([C:15]2[CH:14]=[C:13]([C:12]3[N:11]=[N:10][C:9]([NH2:24])=[N:8][C:7]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:16]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: Nc1nnc(-c2cc(Cl)nc(C(F)(F)F)c2)c(-c2ccccc2)n1
Reactant: C1CNC1
Product: Nc1nnc(-c2cc(N3CCC3)nc(C(F)(F)F)c2)c(-c2ccccc2)n1
Yield: 19 %

Procedure:
6-[2-(Azetidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine (20.0 mg, 19%) was prepared from 5-phenyl-6-(2-chloro-6-trifluoromethyl-pyridin-4-yl)-1,2,4-triazin-3-amine (100 mg, 0.28 mmol) and azetidine according to the general procedure for Preparation 4a.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12](O)(=[O:14])=[O:13])[CH:10]=2)[C:5]([C:16]([OH:18])=[O:17])=[CH:4][NH:3]1.[Cl:19]S(O)(=O)=O>>[Cl:19][S:12]([C:9]1[CH:10]=[C:11]2[C:6]([C:5]([C:16]([OH:18])=[O:17])=[CH:4][NH:3][C:2]2=[O:1])=[CH:7][CH:8]=1)(=[O:14])=[O:13]
Reactant: O=C(O)c1c[nH]c(=O)c2cc(S(=O)(=O)O)ccc12
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1c[nH]c(=O)c2cc(S(=O)(=O)Cl)ccc12
Temperature: 100 °C

Procedure:
1-Oxo-7-sulfo 1,2-dihydroisoquinoline-4-carboxylic acid (5 g) was added to chlorosulphonic acid (25 ml). The mixture was heated at 100° C. for 84 h and then slowly dripped onto ice with sting. The mixture was filtered and the residue was washed with water and ether and dried to yield 7-(chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid as a buff solid (7.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:14]([CH2:22][C:23](OCC)=O)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH:14]2[CH2:22][CH2:23][C:3]3[C:2](=[CH:7][CH:6]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=3)[NH:1]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Product: CCOC(=O)Cc1ccc2c(c1)CCC(c1ccccc1)N2

Procedure:
Using ethyl p-aminophenylacetate and ethyl benzoylacetate as starting materials, treatment was made similarly to Example 1 to obtain aimed product.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]1([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:34][CH2:33][C@@H:32]([N:35]([CH3:37])[CH3:36])[CH2:31]2)=[CH:26][CH:25]=1)=[O:22]>C(#N)C.CN(C=O)C>[CH3:37][N:35]([CH3:36])[C@@H:32]1[CH2:33][CH2:34][N:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:23][C:21](=[O:22])[CH2:20][N:16]3[CH2:15][CH2:14][CH:13]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH2:18][CH2:17]3)=[CH:25][CH:26]=2)[CH2:31]1
Reactant: CN(C)[C@@H]1CCN(c2ccc(NC(=O)CCl)cc2)C1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(C)[C@@H]1CCN(c2ccc(NC(=O)CN3CCC(c4ccccc4)CC3)cc2)C1
Reaction time: 12 h

Procedure:
Cesium carbonate (100 mg) and 4-phenylpiperidine (48 mg) were added to a solution of (R)-2-chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]acetamide (80 mg) in acetonitrile (5 ml) and DMF (1 ml), and the mixture was kept at 65° C. for 12 hours. The mixture was freed of volatile fractions and the residue was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). This resulted in the product with the molecular weight of 406.58 (C25H34N4O); MS (ESI): 407 (M+H+).