Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([SH:21])=[N:14][C:15]([N:18]([CH3:20])[CH3:19])=[N:16][CH:17]=1)=[O:11].II>>[CH3:19][N:18]([CH3:20])[C:15]1[N:14]=[C:13]2[S:21][N:9]([CH2:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:10](=[O:11])[C:12]2=[CH:17][N:16]=1
Reactant: CN(C)c1ncc(C(=O)NCCc2ccccn2)c(S)n1
Agent: II
Product: CN(C)c1ncc2c(=O)n(CCc3ccccn3)sc2n1
Yield: 56.3 %

Procedure:
Using the procedure of Example 20, 7.5 g (24.8 mmol) of 2-dimethylamino-4-mercapto-pyrimidine-5-carboxylic acid (2-pyridin-2-yl-ethyl)-amide were treated with 6.4 g (25.2 mmol) of iodine to give 4.21 g of the title compound after recrystallization from isopropanol, mp 134°-136° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:21](O)=[O:22])[NH:8]2)=[CH:4][CH:3]=1.[N:24]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Cl:1][C:2]1[C:10]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:14])=[C:9]2[C:5]([CH:6]=[C:7]([C:21]([NH2:24])=[O:22])[NH:8]2)=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: CN(c1c(Cl)ccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: CN(c1c(Cl)ccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 101.7 %

Procedure:
To a mixture of 6-chloro-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.69 g), 1H-1,2,3-benzotriazol-1-ol (0.31 g) and N,N-dimethylformamide (10 ml) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.44 g) at room temperature, and the mixture was stirred at 50° C. for 20 min, and allowed to cool to room temperature. 28% Aqueous ammonia (0.30 ml) was added, and the reaction mixture was stirred at room temperature for 2 hr, and acidified with 10% aqueous citric acid solution. The resulting crystals were filtrated, washed with water, and dried to give the title compound (0.70 g, quantitative) as colorless crystals. melting point 225-226° C. (decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]([O:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][N:33]([CH3:60])[C:34](=[O:59])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]([C:51]2[CH:56]=[CH:55][C:54]([NH:57][CH3:58])=[CH:53][CH:52]=2)[C:41](=[O:50])[O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:27][CH2:26]1)=[O:23]>>[C:15]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]([O:24][CH:25]1[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][N:33]([CH3:60])[C:34](=[O:59])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]([C:51]2[CH:56]=[CH:55][C:54]([N:57]([C:11](=[O:13])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:14])[CH3:58])=[CH:53][CH:52]=2)[C:41](=[O:50])[O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:29][CH2:30]1)=[O:23]
Reactant: CNc1ccc(N(CCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)C(=O)OCc2ccccc2)cc1
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN(C(=O)OCc1ccccc1)c1ccc(N(C)C(=O)CCN(C)C(=O)OC(C)(C)C)cc1
Yield: 112.2 %

Procedure:
N-(tert-Butoxycarbonyl)-N-methyl-β-alanine (41 mg, 0.19 mmol) and the compound (150 mg, 0.21 mmol) obtained in Example 97c were used to give the title compound (190 mg; yield, 100%) as a white solid according to the method described in Example 41a.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:10]#[N:11].[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH:7]([N:6]1[C:2]([NH:1][C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:3]([C:10]#[N:11])[CH:4]=[N:5]1)([CH3:9])[CH3:8]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)n1ncc(C#N)c1N
Solvent: c1ccncc1
Product: CC(C)n1ncc(C#N)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 70.3 %

Procedure:
To a solution of 5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile (10.4 g) in pyridine (200 ml) was added triphenylmethyl chloride (23.2 g) at room temperature. The mixture was stirred at 60° C. for 5 hours. The reaction mixture was evaporated under reduced pressure and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and evaporated vacuo. The residue was triturated with diisopropyl ether to give 1-isopropyl-5-tritylamino-1H-pyrazole-4-carbonitrile (19.1 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[O:14][N:13]=[C:12]([NH:15][CH3:16])[N:11]=2)[CH:7]=[CH:8][CH:9]=1.Cl[CH2:18][C:19]1[N:20]([CH3:30])[C:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[N:22][N:23]=1.[NH4+].[Cl-]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[O:14][N:13]=[C:12]([N:15]([CH3:16])[CH2:18][C:19]3[N:20]([CH3:30])[C:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[N:22][N:23]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1c(CCl)nnc1-c1ccncc1
Reactant: CNc1noc(-c2cccc(Cl)c2)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(Cc1nnc(-c2ccncc2)n1C)c1noc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.2 %

Procedure:
NaH (7.0 mg, 0.35 mmol) was added to a solution of 5-(3-chlorophenyl)-N-methyl-1,2,4-oxadiazol-3-amine (60 mg, 0.29 mmol) in DMF (3 ml) at r.t. After 5 min 4-[5-(chloromethyl)-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (60 mg, 0.29 mmol) dissolved in DMF (3 ml) was added. The reaction mixture was stirred for 4 h at r.t. Aq. sat. NH4Cl was added and the mixture was extracted with EA. The organic phase was washed with water and brine, dried and concentrated. Flash chromatography (DCM/MeOH 20:1) afforded 60 mg (54%) of the title compound. 1H NMR: 3.12 (s, 3 H) 3.80 (s, 3 H) 4.94 (s, 2 H) 7.46 (t, 1 H) 7.56 (m, 1 H) 7.58-7.63 (m, 2 H) 7.95 (m, 1 H) 8.06 (t, 1 H) 8.79 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[C:6]=2[CH:7]=1.CC1C2C=C3[C:33]4([C:41]5[C:36](=[CH:37]C=C[CH:40]=5)N[C:34]4=[O:42])COC3=CC=2ON=1.BrCC1CCOCC1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:40][CH:41]4[CH2:36][CH2:37][O:42][CH2:34][CH2:33]4)[C:9]3=[O:17])[C:6]=2[CH:7]=1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: Cc1cc2c(cc1C)C1(CO2)C(=O)Nc2ccccc21
Agent: BrCC1CCOCC1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: Cc1cc2c(cc1C)C1(CO2)C(=O)N(CC2CCOCC2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 4-bromomethyltetrahydropyrane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 5,6-dimethyl-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (55%) as a colorless solid: mp 199-201° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ7.32-7.27 (m, 1H), 7.14-7.12 (m, 1H), 7.05-7.00 (m, 2H), 6.91-6.89 (m, 1H), 6.75 (s, 1H), 6.41 (s, 1H), 4.71 (ABq, 2H), 4.12-3.95 (m, 2H), 3.75-3.54 (m, 2H), 3.39-3.28 (m, 2H), 2.19-2.02 (m, 7H), 1.62-1.28 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.9, 159.1, 142.8, 138.5, 132.6, 129.4, 128.7, 125.8, 124.0, 123.7, 123.2, 111.4, 108.5, 79.9, 67.4, 58.0, 46.0, 33.9, 30.8, 20.3, 19.3; MS (ES+) m/z 364.3 (M+1).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][N:33]([CH3:43])[CH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>C(Cl)Cl>[CH3:43][N:33]([CH3:32])[CH2:34][CH2:35][CH2:36][N:37]1[CH2:38][CH2:39][N:40]([CH:18]=[C:17]2[C:16]3[C:15]([CH3:30])([C:14]4[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]5([CH3:31])[CH:8]([C:13]=4[C:21](=[O:22])[C:20]=3[OH:19])[CH2:9][CH2:10][CH:11]5[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]2=[O:24])[CH2:41][CH2:42]1
Reactant: CN(C)CCCN1CCNCC1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN2CCN(CCCN(C)C)CC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 1-(3-dimethylaminopropyl)piperazine (80 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 603 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][Si:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][O:20][CH2:19][N:10]1[C:11]2[C:18]3[CH:17]=[CH:16][S:15][C:14]=3[CH2:13][C:12]=2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)=[CH:3][CH:4]=2)=[N:9]1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(-c3ccc(O)cc3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 52 %

Procedure:
A mixture of the corresponding inteimmediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.3 g, 0.9 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.33 g, 1.5 mmol), Na2CO3 (2 M, 2.7 mL), and Pd(PPh3)2Cl2 (8 mg, 0.075 mmol) in toluene/ethanol (1:1, 6 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give 4′-[4-(2-Trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pe ntalen-6-yl]-biphenyl-4-ol as brown solid in 52% yield.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C[O-].[Na+].O.O.C([O-])(=O)C.[Zn+2:19].C([O-])(=O)C>CO>[Zn:19].[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: [Zn+2]
Agent: CC(=O)[O-]
Agent: CC(C)C[C@H](N)C(=O)O
Agent: C[O-]
Solvent: O
Solvent: CO
Product: [Zn]

Procedure:
L-Leucine (2.00 g, 15.3 mmol) was added to an MeOH solution of NaOMe (prepared with Na: 0.36 g, MeOH: 50 ml) at 0° C. and stirred. An MeOH solution (30 ml) of zinc acetate dihydrate (1.67 g) was then slowly dropwise added thereto at room temperature. After stirring for 2 hours at that same temperature, the solution was concentrated to half its original volume, followed by the addition of an equal volume of water. The precipitated crystal was recovered by filtration, air dried, and then dried under a reduced pressure (5 mmHg, 80° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[S:10][C:11]([CH:14]=O)=[CH:12][N:13]=2)[CH:3]=1.[NH2:16][C:17]1[C:18]([F:30])=[CH:19][C:20]([F:29])=[C:21]([CH:28]=1)[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23]>>[CH:25]1([NH:24][C:22](=[O:23])[C:21]2[CH:28]=[C:17]([NH:16][CH2:14][C:11]3[S:10][C:9]([NH:8][C:4]4[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=4)=[N:13][CH:12]=3)[C:18]([F:30])=[CH:19][C:20]=2[F:29])[CH2:26][CH2:27]1
Reactant: Cc1ccnc(Nc2ncc(C=O)s2)c1
Reactant: Nc1cc(C(=O)NC2CC2)c(F)cc1F
Product: Cc1ccnc(Nc2ncc(CNc3cc(C(=O)NC4CC4)c(F)cc3F)s2)c1

Procedure:
2-(4-Methylpyridin-2-ylamino)-thiazole-5-carbaldehyde was treated with 5-amino-N-cyclopropyl-2,4-difluorobenzamide (for preparation see Example 18) in a manner similar to Example 1 to afford the title compound. LC/MS; (M+H)+=416.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([CH2:15][NH:16][C:17]([C:19]2[CH:20]=[N:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[N:23][CH:24]=2)=[O:18])[CH2:10]1)=O)(C)(C)C>C(Cl)Cl>[ClH:1].[NH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([CH2:15][NH:16][C:17]([C:19]2[CH:24]=[N:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[N:21][CH:20]=2)=[O:18])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNC(=O)c2cnc(-c3cccc(F)c3)nc2)C1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCC1CCCNC1)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride gas is bubbled into a solution of 3-({[2-(3-fluoro-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (3.76 mmol) in DCM (20 mL) and the reaction is stirred at room temperature for 2 hours. The mixture is concentrated in vacuo to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (piperidin-3-ylmethyl)-amide hydrochloride as a solid. MS 415 (M+H); 1H NMR (300 MHz, CD3OD): δ 1.22-1.50 (m, 2H), 1.68-1.90 (m, H), 1.90-2.06 (bs, 2H), 2.06-2.17 (bs, 6H), 2.73-3.04 (m, 2H), 3.24-3.50 (m, H), 7.24-7.35 (m, H), 7.48-7.60 (m, H), 8.19 (d, H), 8.34 (d, H), 9.23 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14](O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C(=O)(O)[O-].[Na+].[C:22]([O:26][CH3:27])(=[O:25])[CH2:23][SH:24]>S(=O)(=O)(O)O>[CH3:27][O:26][C:22](=[O:25])[CH2:23][S:24][CH:14]1[C:15]2[C:10](=[N:9][C:8]3[C:3]([C:2]=2[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12][CH2:13]1
Reactant: COC(=O)CS
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)CSC1CCCc2nc3ccccc3c(N)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (8.82 g) and methyl thioglycolate (40 ml) was added 40 drops of sulfuric acid. The reaction mixture was stirred at ambient temperature for 3 hrs, poured into an iced sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic extracts were washed with water, saturated sodium chloride, and dried over anhydrous magnesium sulfate. The filtrate was concentrated in vacuo and the residue was triturated with ethyl ether to give 2.79 g of product, mp 175°-183° C. (dec.). Recrystallization from methanol/water gave the analytical sample, mp 194°-196° C. (dec.)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:24]=[C:25]([C:27]#[C:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[N:26]=3)[C:10]([C:13]3[CH:14]=[N:15][N:16]([CH2:18][C:19]([O:21]CC)=[O:20])[CH:17]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[OH-].[Na+].CCOC(C)=O.Cl>C1COCC1.CCO.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:24]=[C:25]([C:27]#[C:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[N:26]=3)[C:10]([C:13]3[CH:14]=[N:15][N:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:17]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cn1cc(-c2cnc(N3CCOCC3)c3nc(C#Cc4ccc5ccccc5n4)cn23)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cn1cc(-c2cnc(N3CCOCC3)c3nc(C#Cc4ccc5ccccc5n4)cn23)cn1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of compound 80c (43.4 mg, 0.0860 mmol) in THF (2 mL) and EtOH (2 mL) was added 1N NaOH (1.00 mL, 1.00 mmol) and the resulting mixture was stirred at rt for 3.5 h. The solvents were removed under reduced pressure. The residue obtained was treated with EtOAc (20 mL) and water (20 mL). The resulting mixture was neutralized with 2N hydrochloric acid. The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound 9. 1H-NMR (DMSO-d6) δ (ppm): 13.24 (br s, 1H), 8.49 (m, 3H), 8.05 (m, 3H), 7.86 (t, J=7.6 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.74-7.61 (m, 2H), 5.08 (s, 2H), 4.22 (m, 4H), 3.82 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H21N2O3 (M+H) 480.2. Found 480.4.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:9])[O:29][CH:26]1[CH2:27][CH2:28][N:23]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:24][CH2:25]1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C=Nc1ccccc1-c1ccccc1
Solvent: CC#N
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(Cc2ccccc2)CC1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
In a 50 ml sealed tube was added 2-biphenylylisocyanate (8 g, 41 mmol) in anhydrous acetonitrile (40 mL). To this solution was added N-benzyl-4-piperidinol (9.8 g, 51.25 mmol) and the tube was partially immersed in a silicon oil bath and heated to 85° C. After 16 h, the reaction mixture was cooled and concentrated in vacuo to give a 1-benzyl-4-piperidyl N-(2-biphenylyl)carbamate which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[C:37]([F:41])=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:10]2[N:6]3[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[C:8]([C:36]3[C:37]([F:41])=[CH:38][C:39]4[C:34]([CH:35]=3)=[N:33][N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:40]=4)[CH:9]=2)[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)CC1
Reactant: CC1(C)OB(c2cc3nn(Cc4ccccc4)cc3cc2F)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3cc4nn(Cc5ccccc5)cc4cc3F)c3c(N)ncnn23)CC1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To the microwave vial was added tert-butyl 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (250 mg, 0.63 mmol), 2-benzyl-5-fluoro-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (300 mg, 0.85 mmol, 1.35 eq), and tetrakis(trephenylphosphine)palladium (0) (46 mg, 0.063 mmol, 0.1 eq). Degassed, anhydrous DMF (6.3 mL) was added followed by 2.0M sodium carbonate solution (1.0 mL). The vial was capped and the reaction was irradiated in a microwave reactor at 180° C. for 25 min. The mixture was cooled to rt, diluted with EtOAc and filtered through a pad of Celite® to remove excess palladium. The filtrate was washed with 50% aqueous brine (3×), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by ISCO® (gradient elution 0 to 10% MeOH/DCM) to give the product (309.7 mg, 68%) as an oil. 1H-NMR (300 MHz, CD3OD) 8.35 (s, 1H), 7.84 (s, 1H), 7.63 (d, 1H), 7.56 (d, 1H), 7.38 to 7.31 (m, 5H), 6.59 (s, 1H), 5.65 (s, 2H), 4.23 to 4.17 (m, 2H), 3.48 to 3.39 (m, 1H), 2.95 (broad s, 2H), 2.12 (d, 2H), 1.72 to 1.59 (m, 2H), 1.47 (s, 9H); ES-MS m/z 542.3 [M+H]+, RT (min) 3.10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][CH2:16][F:17])[CH:7]=[C:6]2[C:18]1[N:26](S(C2C=CC(C)=CC=2)(=O)=O)[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1.[OH-].[K+]>>[F:17][CH2:16][CH2:15][CH2:14][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2)[C:6]([C:18]2[NH:26][C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=2)=[CH:7]1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCF)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4cccnc4[nH]3)cn(CCCF)c2cc1OC
Yield: 27.4 %

Procedure:
2-[1-(3-fluoropropyl)-5,6-dimethoxy-1H-indol-3-yl]-1H-pyrrolo[2,3-b]pyridine is prepared by following the procedure described in example 88a, but using 0.042 g of 2-[5,6-dimethoxy-1-(3-fluoropropyl)indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 1.63 ml of a 5N aqueous potassium hydroxide solution. After purification by flash-pack chromatography (silica, 98/02 by volume dichloromethane/methanol as eluents), 0.008 g of 2-[1-(3-fluoropropyl)-5,6-dimethoxy-1H-indol-3-yl]-1H-pyrrolo[2,3-b]pyridine is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(Cl)[Cl:11]>>[Cl:11][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ncccc1CO
Reactant: ClCCl
Product: Cc1ncccc1CCl

Procedure:
To a stirring solution of crude (2-methylpyridin-3-yl)methanol in 20 mL of CH2Cl2 was added 2.2 mL of SO2Cl2. After 17 h the solution was concentrated and CH2Cl2 and saturated NaHCO3 were added. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (1% MeOH/CHCl3) provided 1.18 g of 3-(chloromethyl)-2-methylpyridine as yellow-orange oil.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=2[O:29][CH3:30])[C:14]([NH:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[O:15])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33]1(S(Cl)(=O)=O)C=CC=C[CH:34]=1>>[CH2:33]([O:22][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][C:17]([NH:16][C:14](=[O:15])[C:13]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:11]([NH:10][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:12]=2)=[CH:18][CH:19]=1)[CH3:34]
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(NS(=O)(=O)c2ccccc2)c1OC
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(NS(=O)(=O)c3ccccc3)c(OC)c(OC)c2)cc1

Procedure:
4-[3-(benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid, MS (ISP): m/e=455.2 (M−H), was prepared in analogy to example 31, steps A to D. Step C was performed using benzenesulfonyl chloride and yielded 4-[3-(benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:17]=[C:18]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-])=O)[CH:27]=4)[C:19]4[S:24][CH:23]=[CH:22][C:20]=4[N:21]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1>C(O)C.[Fe]>[NH2:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[O:25][C:18]1[C:19]2[S:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([N:6]3[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]3)=[CH:14][CH:13]=2)[N:17]=1
Reactant: CN1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)c4sccc4n3)cc2)CC1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CN1CCN(c2ccc(Nc3nc(Oc4cccc(N)c4)c4sccc4n3)cc2)CC1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
Iron (27.1 mmol) and 12 N HCl aqueous solution (2.17 mmol) were diluted with 50% ethanol aqueous solution (30 mL), followed by stirring at 100° C. for 10 min. The compound (5.42 mmol) obtained in Step 4 was dissolved in 50% ethanol aqueous solution (30 mL) and then added to the reaction flask in which iron was activated, followed by stirring at 100° C. for 1 hour. After the reaction was complete, the reaction mixture was filtered with celite to remove iron, and the filtrate was distilled under a reduced pressure. The residue was distilled with dichloromethane and washed with sat. NaHCO3 aqueous solution. The organic layer was dried with anhydrous sodium sulfate and then filtered and distilled under a reduced pressure. The residue was separated by column chromatography (dichloromethane:methanol=10:1 (volume ratio)) to obtain the title compound (yield: 67.8%).