Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+](N[C:22]1[NH:27][C:26](=[O:28])[C:25]([CH2:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[CH:24][N:23]=1)([O-])=O>N1C=CC=CC=1>[C:6]1([N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:22]2[NH:27][C:26](=[O:28])[C:25]([CH2:29][C:30]3[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=3)=[CH:24][N:23]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: NCCCN(c1ccccc1)c1ccccn1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCN(c3ccccc3)c3ccccn3)[nH]c2=O)cn1

Procedure:
To a suspension of sodium hydride (0.78 g) in DMSO (20 ml) was added 2-(N-phenylamino)pyridine (5.0 g) in DMSO (15 ml). The mixture was stirred and slowly heated under nitrogen to 85° C. After the evolution of hydrogen had ceased the mixture was cooled to room temperature and N-(3-bromopropyl)phthalimide (7.88 g) in DMSO (15 ml) added dropwise. After standing overnight the mixture was poured into water and ether extracts made with the pH adjusted between 2 to 4. The extracts were dried (MgSO4), stripped and the residue crystallised from ethanol to give N-[3-(N-phenyl-N-pyrid-2-ylamino)propyl]phthalimide, 3.69 g (35%) mp 103°-5° C. (ii) N-[3-(N-phenyl-N-pyrid-2-ylamino)propyl]phthalimide (3.1 g) and conc. hydrochloric acid (30 ml) were heated under reflux for 21 hr. Phthalic acid was filtered off on cooling and the filtrate stripped. The residue was taken back up in water and the solution extracted at pH 1 with chloroform. The pH was raised to 13 (NaOH) and the solution extracted again with ether. The ether extracts were dried (K2CO3) and stripped to give 2-[N-(3-aminopropyl)-N-phenylamino]pyridine, 1.84 g as an oil. (iii) 2-[N-(3-aminopropyl)-N-phenylamino]pyridine (0.9 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (0.86 g) were heated together under reflux in pyridine (2.5 ml) for 24 hr. The mixture was stripped and the residue recrystallised from ethanol to give 2-[3-(N-phenyl-N-pyrid-2-ylamino) propylamino]-5-(6-methylpyrid-3-ylmethyl) pyrimid-4-one, 1.03 g (73%) mp 216°-18° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:15]=[CH:14][C:13]=2[N+:22]([O-:24])=[O:23])[OH:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:15]=[CH:14][C:13]=2[N+:22]([O-:24])=[O:23])=[O:11])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: C#CCOc1ccc([N+](=O)[O-])c(C(O)c2ccc(C(C)C)cc2)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C#CCOc1ccc([N+](=O)[O-])c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice cold solution of (4-isopropyl-phenyl)-(2-nitro-5-propargyloxy-phenyl)-methanol in 200 ml acetone are added dropwise 60 ml Jones reagent. After stirring for 2 h at rt the reaction is quenched by the addition of isopropanol and sodium bisulfite solution (40%). Extraction with dichloromethane affords (4-isopropyl-phenyl)-(2-nitro-5-propargyloxy-phenyl)-methanone.
Reaction SMILES: C([O:5][C:6](=[O:48])[C@H:7]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:8][C:9](=[O:40])[CH2:10][N:11]([C:21](=[O:39])[C@H:22]([CH3:38])[NH:23][C@@H:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)(C)(C)C.[BrH:49].CCOCC>C(O)(=O)C>[BrH:49].[CH2:36]([O:35][C:33]([C@H:24]([NH:23][C@H:22]([C:21]([N:11]([CH:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20]1)[CH2:10][C:9]([NH:8][C@H:7]([C:6]([OH:48])=[O:5])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:40])=[O:39])[CH3:38])[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:34])[CH3:37]
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)N[C@@H](Cc1ccccc1)C(=O)O)C1Cc2ccccc2C1

Procedure:
N-[1(R)-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(2-indanyl)glycyl-L-phenylalanine tert-butyl ester (0.2 g) is dissolved in 0.5 ml of acetic acid and shaken with 1 ml of 30% hydrogen bromide in acetic acid for 10 minutes, followed by addition of 50 ml of ether and 50 ml of petroleum ether. The supernatant is decanted off and petroleum ether is added to the residue. The solid substance is collected by filtration and dried to give 0.18 g of N-[1(R)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(2-indanyl)glycyl-L-phenylalanine hydrobromide as powder.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:22][OH:23]>>[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:22][O:23][C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1cccc(F)c1F
Product: CN1CCCn2c1cc(OCc1cccc(F)c1F)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (2,3-difluorophenyl)methanol.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[N:7]=[C:8]([CH2:16][CH2:17][CH3:18])[NH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:5])[CH3:4].CC(C)=O>C(O)C>[OH:5][CH:3]([C:6]1[N:7]=[C:8]([CH2:16][CH2:17][CH3:18])[NH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:4]
Reactant: CCCc1nc(C(C)=O)c(C(=O)OCC)[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCCc1nc(C(C)O)c(C(=O)OCC)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
125 mg of sodium borohydride were added to a solution of 1.50 g of ethyl 4-acetyl-2-propylimidazole-5-carboxylate [prepared as described in step (ii) above] in 15 ml of ethanol, and the resulting mixture was stirred at room temperature for 30 minutes. 2 ml of acetone were added, and the mixture was stirred for a further 10 minutes. The reaction mixture was then concentrated by evaporation under reduced pressure, and the concentrate was dissolved in methanol. The solution was again concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using 1:20 and 1:10 by volume mixtures of methylene chloride and methanol as the eluent, to give 1.32 g of the title compound as crystals, melting at 151°-153° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C([N:17]=[C:18]=[S:19])(=O)C1C=CC=CC=1>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:18]([NH2:17])=[S:19])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1cccc(N)n1
Solvent: CCO
Product: Cc1cccc(NC(N)=S)n1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
6-Methyl-pyridin-2-ylamine (1.0 g, 9.2 mmol) is dissolved in ethanol (10 ml) and benzoylisothiocyanate (1.24 ml, 9.2 mmol) is added dropwise. The mixture is heated to 40° C. with stirring for 10 minutes then allowed to cool to room temperature. The solvent is removed in vacuo and the resulting solid dissolved in 1M sodium hydroxide (15 ml) and heated under reflux for 2 hour. The resultant suspension is filtered and the solid washed copiously with water and then with cold ethanol. The solid is dried in vacuo to yield the title compound. Mass Spec (APCI+) 168.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[C:15]([N:16](COC)[S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)(=[O:19])=[O:18])=[CH:14][C:13]([Cl:34])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>N1C=CC=CC=1>[Cl:34][C:13]1[CH:14]=[C:15]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=2)(=[O:19])=[O:18])[C:10]([C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[CH:7]=2)=[O:9])=[N:11][CH:12]=1
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccnc(N)c1)S(=O)(=O)c1ccc(C)c(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc(NS(C)(=O)=O)c2)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
To a solution of N-[2-(2-amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamide (140 mg, 0.272 mmol) in pyridine (0.75 mL) was added methanesulfonyl chloride (0.042 mL, 0.544 mmol). The reaction was warmed to 50° C. and stirred 2.5 h. The resultant mixture was quenched with 10% HCl, diluted with EtOAc, and the organic layer washed with 10% HCl and saturated sodium bicarbonate. The combined organics were dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to produce the desired sulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:15](=[O:25])[CH2:14][CH2:13][CH2:12]1.Br[CH2:27][CH2:28][CH3:29]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:27][CH2:28][CH3:29])=[CH:20][CH:19]=2)[C:15](=[O:25])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(O)cc1
Reactant: CCCBr
Product: CCCOc1ccc(CN2C(=O)CCCC2c2c(OC)cccc2OC)cc1

Procedure:
Prepared according to the described general procedure 7 (GP7) by O-alkylation of 6-(2,6-dimethoxyphenyl)-1-(4-hydroxybenzyl)piperidin-2-one with commercially available 1-bromopropane. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.79 min.; [M+H]+: 384.19 g/mol.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[CH:7]=[C:6]([N:10]2[CH:14]=[C:13](I)[N:12]=[C:11]2[CH3:16])[CH:5]=[N:4]1)[CH3:2].[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)#[CH:18]>>[CH2:1]([N:3]1[C:8](=[O:9])[CH:7]=[C:6]([N:10]2[CH:14]=[C:13]([C:18]#[C:17][C:19]3[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)[N:12]=[C:11]2[CH3:16])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(-n2cc(I)nc2C)cc1=O
Reactant: C#Cc1cccc(C)c1
Product: CCn1ncc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O

Procedure:
The title compound, light brown crystalline solid, MS: m/e=319.1 (M+), was prepared in accordance with the general method of example 21a from 2-ethyl-5-(4-iodo-2-methyl-imidazol-1-yl)-2H-pyridazin-3-one and 1-ethynyl-3-methyl-benzene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](OCC2C=CC=CC=2)=[C:9]([O:21][CH3:22])[CH:8]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:33]([O:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][O:49]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:43][CH:42]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>C(#N)C>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:49][CH2:48][CH2:47][C:44]2[CH:43]=[CH:42][C:41]([NH:40][C:38]([O:37][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:39])=[CH:46][CH:45]=2)=[C:9]([O:21][CH3:22])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)c(OC)c1)OCC
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)c(OC)c1)OCC
Yield: 77.2 %

Procedure:
3-(4-Benzyloxy-3-methoxyphenyl)-2-ethoxypropanoic acid ethyl ester (0.5 g; 1.86 mmole) was dissolved in acetonitrile and potassium carbonate (0.53 g; 3.91 mmole) was added. 2-[4-(tert-Butoxycarbonylamino)phenyl]ethyl-4-methylbenzenesulfonate (described in Example 40a) (0.755 g, 1.92 mmole) was added. The resulting mixture was stirred and refluxed over night then filtered and the filtrate was evaporated. The residue was treated with sodium hydroxide (0.5 M) and diethyl ether. The phases were separated and the organic phase was dried with magnesium sulfate. Evaporation gave 0.7 g (77.2% yield) of 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]-3-methoxyphenyl}-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][O:8][C:9](=[O:13])[N:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1.[CH3:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][C:24]=1[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=1)=[O:19]>>[CH3:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][C:24]=1[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[CH2:6][CH2:7][O:8][C:9](=[O:13])[N:10]([CH2:11][CH3:12])[C:4]=3[CH:3]=2)[N:27]=1)=[O:19]
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)OCCc2ccc(N)cc21
Product: CCN1C(=O)OCCc2ccc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)cc21

Procedure:
Following a procedure analogous to Example 1741e, 3-amino-5-ethyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and 3-(2,5-dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide were converted to 3-[5-chloro-2-(5-ethyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-thiophene-2-carboxylic acid methylamide. TFA salt: 1H NMR (300 MHz, CDCl3) δ 11.42 (s, 1H), 8.35 (d, 1H), 8.22 (s, 1H), 7.80 (s, 1H), 7.41 (s, 1H), 7.28 (d, 1H), 7.22 (d, 1H), 7.04 (s, 1H), 4.80 (bq, 1H), 4.60 (t, 2H), 3.90 (q, 2H), 3.12 (d, 3H), 3.06 (t, 2H), 1.26 (t, 3H); MS (m/e) 473 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][C:46]=2B(O)O)[CH:41]=[CH:40]1.C(=O)([O-])[O-].[Na+].[Na+]>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>[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][C:46]=2[C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:41]=[CH:40]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1cccc2cc[nH]c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cccc5cc[nH]c35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 84.9 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with (1H-indol-7-yl)boronic acid (65 mg, 0.28 mmol), sodium carbonate (43 mg, 0.40 mmols) and bis(triphenylphosphine)palladium(II) dichloride (12 mg, 0.02 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 25%, hexane-ethyl acetate) to give 91 mg (81% yield) of the title compound. Purity 94%.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[C:7]([S:14]([NH2:17])(=[O:16])=[O:15])=[C:8]([N+:11]([O-])=O)[S:9][CH:10]=1>C(O)(=O)C.[Fe]>[NH2:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][O:4][CH2:3][O:2][CH3:1])[C:7]=1[S:14]([NH2:17])(=[O:15])=[O:16]
Reactant: COCOCc1csc([N+](=O)[O-])c1S(N)(=O)=O
Agent: [Fe]
Solvent: CC(=O)O
Product: COCOCc1csc(N)c1S(N)(=O)=O
Yield: 61.9 %

Procedure:
The product of Example 309F (1.8 g, 6.4 mmol) was reacted with iron powder (1.43 g, 4 equivalents) in acetic acid (70 mL) at 50° C. for 7.5 hours then concentrated under reduced pressure. A slurry of the residue in 5% methanol/dichloromethane (60 mL) and water (6 mL) was filtered through silica gel (20 g) and further rinsed with 5% methanol/dichloromethane (300 mL). The filtrate was concentrated under reduced pressure and the residue purified by flash chromatography on silica gel using a Biotage-12s column eluting with 2.5:97.5 methanol: dichloromethane to give the title compound (1 g, 62%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.30 (s, 3 H), 4.53 (s, 2 H), 4.66 (s, 2 H), 6.28 (s, 1 H), 6.61 (s, 2 H), 6.94 (s, 2 H).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]([NH2:30])=[N:8][C:9]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[N:14]=3)=[N:10][C:11]=2[NH2:12])[CH2:4][CH2:3][CH2:2]1.C1N=CN([C:36](N2C=NC=C2)=[O:37])C=1.C(N(CC)CC)C>CN(C)C=O>[NH2:12][C:11]1[N:10]=[C:9]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:14]=2)[N:8]=[C:7]2[C:6]=1[N:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)[C:36](=[O:37])[NH:30]2
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1NC1CCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)n(C3CCC3)c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
133 mg (0.26 mmol) of the compound from example 65A were initially charged in dimethylformamide (1.4 ml), then 213 mg (1.32 mmol) of N,N-carbonyldiimidazole and 0.44 ml (3.16 mmol) of triethylamine were added and the mixture was stirred at 100° C. overnight. Thereafter, another 200 mg (1.23 mmol) of N,N-carbonyldiimidazole were added and the mixture was again stirred at 100° C. overnight. The reaction mixture was purified directly by means of preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid gradient). This gave 79 mg (68% of theory) of the title compound in solid form.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1.CN(C=O)C>C1COCC1>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][N:16]=[C:15]2[CH:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11]
Reactant: O=C1Cc2ccc(F)cc2N1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3C(=O)Nc4cc(F)ccc43)c2cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.8 %

Procedure:
A solution of 6-fluorooxindole (264 mg, 1.75 mmol), (prepared according to Synthesis 1993, 51), in THF (3 ml) was added dropwise under nitrogen to sodium hydride (42 mg, 1.75 mmol, pre-washed with hexane). After stirring the resulting mixture for 20 minutes at ambient temperature, 4-chloro-6,7-dimethoxyquinazoline (210 mg, 0.93 mmol), (prepared as described for the starting material in Example 1), was added as a solid, followed by DMF (4 ml). The reaction mixture was then heated at 85° C. for 1 hour, the solvent was removed by evaporation and the residue partitioned between ether and water. The aqueous layer was separated and neutralised with 2M hydrochloric acid and the solid was collected by filtration, washed with ether and dried under vacuum to give 6,7-dimethoxy4-(6-fluorooxindol-3-yl)quinazoline (255 mg, 81%) as a yellow solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:26])=[C:7]([CH:25]=1)[NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:10]=1.[C:27](O)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:26][C:6]1[CH:5]=[CH:4][C:3]([NH:2][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][C:7]=1[NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[N:12]=[C:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:10]=1
Reactant: Cc1ccc(N)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccccc2)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.5 %

Procedure:
A mixture of 4-(5-amino-2-methylanilino)-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine hydrochloride (25 mg, 0.067 mmol), benzoic acid (10 mg, 0.080 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15.4 mg, 0.080 mmol) in dichloromethane (5 ml) was stirred at room temperature for 24 h. The mixture was rotary evaporated to dryness and the residue was purified by column chromatography to give a white solid (14 mg, 47%). 1H NMR (CDCl3): 9.66 (s, 1H), 8.75–8.71 (m, 1H), 8.67 (bs, 1H), 8.40 (s, 1H), 8.08 (dd, J=1.2, 8.4 Hz, 1H), 7.93 (d, J=1.8 Hz, 1H), 7.90–7.86 (m, 2H), 7.81 (s, 1H), 7.55–7.38 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 6.71 (s, 1H), 2.23 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:10]=[N+]=[N-])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4].C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH2:10])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4]
Reactant: COC(=O)C1CC(N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CC(N)CN1C(=O)OC(C)(C)C

Procedure:
A solution of 4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, THF and PPh3 and water is refluxed for about 6 hours and then concentrated. The residue is dissolved in Et2O and treated with HCl. The aqueous layer is extracted, washed, dried and concentrated to afford 4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (32).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH3:16])[NH:8]2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[NH:8]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCCCC=Cc1cc2ccc(Cl)cc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCc1cc2ccc(Cl)cc2[nH]1
Reaction time: 5 h

Procedure:
6-Chloro-2-hex-1-enyl-1H-indole was dissolved in ethanol and 10% palladium on carbon was added to the solution. The reaction flask was sealed and exposed to hydrogen gas under pressure and was stirred for 5 hours. Then the reaction mixture was filtered through Celite. The solvent was evaporated to give 6-Chloro-2-hexyl-1H-indole.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:28])[C:8]=1[NH:9][C:10]([C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH2:26][CH3:27])=[N:17][N:18]2[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1)=[O:11].I[CH3:30]>CN(C=O)C.O>[Cl:28][C:7]1[CH:6]=[N:5][CH:4]=[C:3]([Cl:2])[C:8]=1[N:9]([CH3:30])[C:10]([C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH2:26][CH3:27])=[N:17][N:18]2[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1)=[O:11]
Reactant: CI
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3c(Cl)cncc3Cl)ccc12
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(C2CCCC2)c2cc(C(=O)N(C)c3c(Cl)cncc3Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
5.2 mg (0.130 mmol, 1.05 equiv) sodium hybride, 60% oil dispersion, were added to a room temperature solution of 50 mg (0.124 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid (3,5-dichlor-pyridin-4-yl)-amide in 3 mL anhydrous DMF. After 30 min. 7.7 μl (0.124 mmol, 1.0 equiv) iodomethane were added and the mixture stirred at room temperature for 4 h. The reaction mixture was diluted with 50 mL H2O and extracted 2×20 mL ethyl acetate. The ethyl acetate extracts were combined, washed 2×5 mL H2O, 1×5 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave a yellow oil, which was purified on a silica gel column (25% ethylacetate/hexanes, flash) to give 27 mg (52%) of a white crystalline solid: mp 118-119° C.; HRMS calcd for C21H22N4OCl3+H: 417.12519. Found: 417.12270.