Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[N+:1]([C:4]1[CH:10]=[C:9]([C:14]2[CH:13]=[CH:12][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc2ccccc2c1
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: Cc1ccccc1
Product: Nc1ccc(-c2ccc3ccccc3c2)cc1[N+](=O)[O-]
Yield: 68 %

Procedure:
A suspension of 2-nitro-4-bromoaniline (5 g, 23 mmol) in toluene is admixed with 3.27 g (23 mmol) of 2-naphthylboronic acid, 9.5 g (0.069 mol) of potassium carbonate and 1.3 g of tetrakis(triphenylphosphine)palladium. The mixture is heated to reflux for 4 hours and the reaction is stopped by adding 100 ml of water. The mixture is extracted with ethyl acetate and dried over sodium sulphate, and the solvent is removed under reduced pressure. Purification by column chromatography gives 4.1 g (68% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[S:24]([CH3:23])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(NCc2cccnc2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)c1ccc(F)cc1F
Temperature: 25 °C

Procedure:
A 8.9 g. portion of 3-(2,4-difluorophenylaminomethyl)pyridine was dissolved in 30 ml. of dichloromethane, and to it was added 6.9 g. of potassium carbonate and 3.9 ml. of methanesulfonyl chloride. The mixture was stirred at ambient temperature for several days, and then was heated and stirred at the reflux temperature overnight. It was then cooled, extracted with aqueous sodium bicarbonate, dried over magnesium sulfate and evaporated to a small volume. The residue was chromatographed over silica gel, eluting first with dichloromethane and then with 9:1 dichloromethane:ethyl acetate. The product-containing fractions were combined and evaporated to obtain impure product, which was triturated with diethyl ether and dried to obtain 5.6 g. of the desired product, m.p. 132°-135°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:7][C:6]2=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl.Cl[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>O1CCCC1.C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:7][C:6]2=1
Reactant: ClCc1ccccn1
Reactant: COc1ccc2[nH]c3c(c2c1)CC(NC(=O)C(C)C)CC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c1c(n2Cc2ccccn2)CCC(NC(=O)C(C)C)C1
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
Dissolve N-(6-methoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (200 mg, 0.70 mmol) in anhydrous tetrahydrofuran (6 mL) under nitrogen. Add dropwise potassium bis(trimethylsilyl)amide (3.2 mL, 1.6 mmol, 0.5M in toluene) and stir 30 min. Add slowly 2-(chloromethyl)pyridine hydrochloride (131 mg, 0.80 mmol) in THF/DMF (0.4 mL/1.3 mL) and stir at ambient temperature for 18 h. Quench with saturated ammonium chloride solution (0.5 mL) and partition between ethyl acetate and water. Separate the two phases and wash the aqueous phase with ethyl acetate (2×). Dry the combined organic portions (MgSO4), filter, and concentrate in vacuo to obtain a residue. Purify the material by silica gel chromatography, eluting with 50% ethyl acetate/dichloromethane with a gradient up to 80% ethyl acetate/dichloromethane to obtain 199 mg (75%) of a light yellow solid. MS (ES): m/z 378 (M+1); 1H NMR(DMSO-d6): δ 8.50 (dd, 1H, J=4.8, 0.9 Hz), 7.82 (d, 1H, J=7.5 Hz), 7.65 (dt, 1H, J=7.6, 1.6 Hz), 7.22 (m, 2H), 6.89 (d, 1H, J=2.2 Hz), 6.77 (d, 1H, J=7.9 Hz), 6.63 (dd, 1H, J=8.6, 2.4 Hz), 5.32 (s, 2H), 3.97 (m, 1H), 3.72 (s, 3H), 2.91 (dd, 1H, J=15.0, 5.3 Hz), 2.85-2.76 (m, 1H), 2.74-2.64 (m, 1H), 2.45 (m, 1H), 2.37 (m, 1H), 1.94 (m, 1H), 1.77 (m, 1H), 0.99 (m, 6H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]([C@H:8]2[CH2:12][C@@H:11]([N:13]3[CH:21]=[N:20][C:19]4[C:14]3=[N:15][C:16](N[C@@H]3CCNC3)=[N:17][C:18]=4[NH:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:10]([OH:37])[C@@H:9]2[OH:38])[CH:7]=1)[CH3:2].F[C:40](F)(F)C(O)=O.O[C@@H]1[C@H](O)[C@@H](N2C=C(C)C=N2)C[C@H]1N1C=NC2C1=NC(NC1CCC(NC(NC3CCN(C4C=CC=CN=4)CC3)=O)CC1)=NC=2NCC(C1C=CC=CC=1)C1C=CC=CC=1.[CH:106]([N:109]([CH:120]([CH3:122])[CH3:121])[CH2:110][CH2:111][NH:112][C:113]([N:115]1[CH:119]=[CH:118][N:117]=[CH:116]1)=[O:114])([CH3:108])[CH3:107]>>[CH:106]([N:109]([CH:120]([CH3:122])[CH3:121])[CH2:110][CH2:111][NH:112][C:113]([NH:115][C@@H:119]1[CH2:40][CH2:116][N:117]([C:16]2[N:15]=[C:14]3[C:19]([N:20]=[CH:21][N:13]3[C@@H:11]3[CH2:12][C@H:8]([N:6]4[CH:7]=[C:3]([CH2:1][CH3:2])[CH:4]=[N:5]4)[C@@H:9]([OH:38])[C@H:10]3[OH:37])=[C:18]([NH:22][CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:17]=2)[CH2:118]1)=[O:114])([CH3:108])[CH3:107]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C(C)C
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCCc5ccccc5)nc(N[C@@H]5CCNC5)nc43)[C@H](O)[C@@H]2O)c1
Agent: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCC(NC(=O)NC6CCN(c7ccccn7)CC6)CC5)nc43)[C@H](O)[C@@H]2O)c1
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCCc5ccccc5)nc(N5CC[C@@H](NC(=O)NCCN(C(C)C)C(C)C)C5)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
This compound is prepared from (1S,2R,3S,5R)-3-(4-ethyl-pyrazol-1-yl)-5-[6-phenethylamino-2-((R)-pyrrolidin-3-ylamino)-purin-9-yl]-cyclopentane-1,2-diol (Example 55) using a procedure analogous to that of 1-{4-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-methyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-ylamino]-cyclohexyl}-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-urea trifluoroacetate (Example 42) replacing N-[1-(2-pyridinyl)-4-piperidinyl]-1H-imidazole-1-carboxamide with imidazole-1-carboxylic acid (2-diisopropylamino-ethyl)-amide. MS (ES+) m/e 688 (MH+).
Reaction SMILES: [CH:1]1([S:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:16]OS([O-])=O.[K+].[OH2:22]>CO>[CH:1]1([S:6]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)(=[O:16])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O
Reactant: O=[N+]([O-])c1ccc(SC2CCCC2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(S(=O)(=O)C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Intermediate 1 (0.7 g) was dissolved in methanol (20 ml) and the solution cooled to 0° C. A solution of oxone (1.93 g) in water (20 ml) was added and the mixture was stirred under nitrogen for 2 h at room temperature. The mixture was extracted with dichloromethane, the layers were separated (hydrophobic frit), and the organic layer evaporated to give the title compound as a yellow oil which crystallised on standing (0.79 g).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:25])[CH2:9][N:10]2[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][C:11]2=3)=[CH:4][CH:3]=1.[CH3:26][N:27](C=O)C>CCOC(C)=O.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.[C-]#N.[Zn+2].[C-]#N>[CH3:24][N:21]1[CH2:22][CH2:23][C:11]2[N:10]([CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([C:26]#[N:27])=[N:7][CH:6]=3)[OH:25])[C:18]3[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[C:12]=2[CH2:20]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(Br)nc2)CCN(C)C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(C#N)nc2)CCN(C)C1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a degassed solution of 1-(6-bromo-pyridin-3-yl)-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethanol (1 g, 2.5 mmol) in DMF (10 mL) were added Pd(PPh3)4 (0.173 g, 0.15 mmol) and zinc cyanide (585 mg, 5.0 mmol) and the reaction mixture was stirred at 150° C. for 2 h. The reaction mixture was cooled to RT, diluted with EtOAc (250 mL) and filtered. The filtrate was washed with water (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 5-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-pyridine-2-carbonitrile (350 mg). 1H NMR (CDCl3, freebase) δ (ppm): 8.55 (s, 1H), 7.38 (d, 1H), 7.23 (d, 1H), 6.93 (s, 1H), 6.81 (s 1H), 6.74 (s, 1H), 4.96 (m, 1H), 4.11 (dd, 2H), 3.29 (dd, 2H), 2.95 (m, 1H), 2.88 (m 1H), 2.86 (m, 2H), 2.5 (s, 6H). Separation by chiral HPLC provided enantiomers 140a and 140b.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]([CH3:30])[CH2:25][C:26](=[O:29])[NH:27][N:28]=2)=[CH:19][CH:18]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]([CH3:30])[CH2:25][C:26](=[O:29])[NH:27][N:28]=2)=[CH:19][CH:18]=1)=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCSC1C(=O)O
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: C1CCOC1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)C2SCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7.5 g (0.032 mole) of 3-tert.-butoxycarbonyl-thiazolidine-2-carboxylic acid and 5.2 g (0.032 mole) of N,N'-carbonyl-diimidazole are heated under reflux in 50 ml of tetrahydrofuran for 15 minutes. After addition of 6.1 g (0.03 mole) of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone, the mixture is stirred at room temperature for 18 hours and concentrated and the residue is crystallised with ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:6](=[O:13])[NH:5][C:4](=[O:14])[CH:3]=1.Cl.[N:16]([O-])=[O:17].[Na+]>CS(C)=O.O>[NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:11])([CH3:10])[CH3:12])[C:6](=[O:13])[NH:5][C:4](=[O:14])[C:3]=1[N:16]=[O:17]
Reactant: O=N[O-]
Reactant: CC(C)(C)Cn1c(N)cc(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)Cn1c(N)c(N=O)c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7.0 g of XXVI in 50 ml of DMSO was added 8 ml of 5N HCl and 2.7 g of NaNO2 dissolved in 5 ml of water. The reaction mixture was stirred 10 minutes at 50° C. and then 100 ml of water was added. The red crystals were filtered off. Yield 6 g (XXVII).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:14]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]=[C:12]([C:24]#[C:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[N:7]=1.Cl>CO.O1CCOCC1.CO.CS(C)=O>[CH2:17]([O:16][CH2:15][N:14]1[C:3]2[C:2]([NH2:1])=[N:7][C:6]([CH2:8][CH2:9][CH2:10][CH3:11])=[N:5][C:4]=2[C:12]([C:24]#[C:25][CH2:26][N:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]2)=[CH:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCc1nc(N)c2c(n1)c(C#CCN1CCN(C(=O)OC(C)(C)C)CC1)cn2COCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CCCCc1nc(N)c2c(n1)c(C#CCN1CCNCC1)cn2COCc1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 54.9 %

Procedure:
To a solution of tert-butyl 4-(3-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)prop-2-yn-1-yl)piperazine-1-carboxylate (85 mg, 0.160 mmol) in anhydrous methanol (5 mL) was added 4M hydrogen chloride in 1,4-dioxane (0.5 ml, 2.0 mmol). The reaction was stirred at room temperature for 19 hours. A further 0.5 mL (2.0 mmol) of 4M hydrogen chloride in 1,4-dioxane was added to the reaction. Reaction stirred at room temperature for 2 hours. The reaction was evaporated to dryness under a stream of nitrogen to yield a green oil. The oil was dissolved in MeOH:DMSO (1:1) (2×1 mL) and purified by MDAP (Method B). Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a pale yellow oil (38 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-])=O.CO>[Fe].O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[NH2:12]
Reactant: COCSc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CO
Solvent: O
Product: COCSc1ccc(N)c(N)c1

Procedure:
1.3 G. of 1-amino-2-nitro-4-methoxymethylthiobenzene is treated in 80 ml. methanol and 20 ml. water at reflux under nitrogen, with 0.7 g. ferrous sulfate and 2.8 g. iron (added in two portions) for four hours. The mixture is filtered, stripped under vacuum, and the residue recrystallized from cyclohexane. 1,2-Diamino-4-methoxymethylthiobenzene is thus obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.O[C:6]1[C:7]2[C:14]([C:15]3[S:16][CH:17]=[CH:18][N:19]=3)=[CH:13][S:12][C:8]=2[N:9]=[CH:10][N:11]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:3][C:6]1[C:7]2[C:14]([C:15]3[S:16][CH:17]=[CH:18][N:19]=3)=[CH:13][S:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: O=S(Cl)Cl
Reactant: Oc1ncnc2scc(-c3nccs3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ncnc2scc(-c3nccs3)c12
Temperature: 73 °C
Yield: 27.1 %

Procedure:
A mixture of thionyl chloride (15 ml, 200 mmol), 4-hydroxy-5-(thiazol-2-yl)thieno[2,3-d]pyrimidine (1.44 g, 12 mmol) and N,N-dimethylformamide (3 mL) was heated at 73° C. for 3 hours and then carefully poured into 200 mL of ice/water. The pH was adjusted to between 7 and 8 with sodium bicarbonate and then the product was extracted with ethyl acetate (2×450 mL). The organic fractions were combined, dried (MgSO4) and concentrated. The resulting residue was purified by column chromatography over silica gel using a gradient elution from 10 to 20% ethyl acetate in hexanes to give 0.825 g (53%) of 4-chloro-5-(thiazol-2-yl)thieno[2,3-d]pyrimidine as a brown solid. MS [M+H] 254.0, 1H NMR (400 MHz, 10% CD3OD/CDCl3) δ (ppm) 8.92 (s, 1H), 8.00 (d, J=3.2 Hz, 1H), 7.85 (s, 1H), 7.55 (d, J=3.2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:9](=[O:27])[C:8]=3[CH:7]=[CH:6][N:5]2[CH:28]=1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:29]([N:12]1[C:13]2[C:4]3=[N:3][C:2]([CH3:1])=[CH:28][N:5]3[CH:6]=[CH:7][C:8]=2[C:9](=[O:27])[C@H:10]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:23])[CH3:24])[C@H:11]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:31])[CH3:30]
Reactant: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](OC(=O)C(C)(C)C)C3=O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)N1c2c(ccn3cc(C)nc23)C(=O)[C@H](OC(=O)C(C)(C)C)[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a of 0° C. cooled solution of 7.00 g (18.5 mmol) (8R,9R)-2-methyl-9-phenyl-8-pivaloyloxy-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridin-7-one in toluene (70 ml) is added 4.10 ml (55.5 mmol) acetyl chloride and 7.70 ml (55.5 mmol) triethylamine and the reaction mixture is stirred for 1 h at 0° C. Afterwards further 4.10 ml (55.5 mmol) acetyl chloride and 7.70 ml (55.5 mmol) triethylamine are added to the reaction mixture and it is warmed up to 25° C. and stirred at this temperature for 1 h. Subsequently the reaction is quenched by adding of saturated aqueous ammonium chloride solution. This mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is crystallised from diethyl ether to provide 5.4 g (12.7 mmol/70%) of the title compound as a colourless solid with a melting point of 168–169° C. (diethyl ether).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[Br:13]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C.[Cl-].[Na+].O>[Br:13][C:8]1[C:7]2[C:11](=[CH:12][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)[NH:10][N:9]=1
Reactant: BrBr
Reactant: O=C(O)c1ccc2cn[nH]c2c1
Agent: O=S([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(Br)n[nH]c2c1
Reaction time: 24 h
Yield: 99 %

Procedure:
To a solution of 6-carboxyindazole (4.0 g) in acetic acid (140 ml) was added bromine (1.53 ml), and the mixture was stirred in the dark for 24 hours. After the addition of saturated sodium bisulfite (50 ml) and brine (100 ml), the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. The resulting solid was powdered and vacuum dried to afford 3-bromo-6-carboxyindazole as a light brown solid (5.88 g, 99%), mp >250°.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21]>>[CH3:17][O:16][C:7]1[C:6]([O:18][CH3:19])=[N:5][C:4]2[C:9](=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:3]=2[CH2:2][NH:25][CH2:24][CH2:23][N:22]([CH2:26][CH3:27])[CH2:20][CH3:21])[N:8]=1
Reactant: CCN(CC)CCN
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Product: CCN(CC)CCNCc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12

Procedure:
The title compound can be prepared as described under Example 39 a), that is to say from 5-bromomethyl-2,3-dimethoxy-7-nitro-quinoxaline and 2-diethylaminoethylamine. The title compound is obtained in the form of a colorless oil.
Reaction SMILES: CO.[CH2:3]([O:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21])[CH2:4][CH2:5][CH3:6].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1.C[O-].[Na+]>O>[C:24]1([CH3:23])[CH:29]=[CH:28][C:27]([S:30][C:13]2[C:8]([O:7][CH2:3][CH2:4][CH2:5][CH3:6])=[C:9]([N+:20]([O-:22])=[O:21])[CH:10]=[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=2)=[CH:26][CH:25]=1
Reactant: CCCCOc1cc([N+](=O)[O-])c(OCCCC)cc1Cl
Reactant: Cc1ccc(S)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCOc1cc(Sc2ccc(C)cc2)c(OCCCC)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To 110 parts of methanol was added 51 parts of 2,5-dibutoxy-4-chloronitrobenzene, and the mixture was warmed to 50° C. A methanol (50 parts) solution of 21.5 parts of p-thiocresol and 9.8 parts of sodium methylate was added dropwise thereto over a period of about one hour to carry out a reaction therebetween. After completion of the dropwise addition, the reaction was further continued under reflux for 5 hours. After completion of the reaction, 85 parts of water was added to the reaction mixture to precipitate a crystal. The crystal was recovered by filtration and recrystallized from methanol to obtain 58.5 parts of 4-tolylthio-2,5-dibutoxynitrobenzene (m.p.: 44° to 45° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[N:26]=1.O>CN(C)C=O>[Br:24][C:25]1[N:26]=[C:27]([CH2:31][N:9]2[C:10]3[C:15](=[N:14][CH:13]=[CH:12][CH:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:18]=[CH:19][C:20]([CH3:21])=[C:2]([CH3:1])[CH:3]=3)=[CH:8]2)[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1ccc(C(=O)c2c[nH]c3cccnc3c2=O)cc1C
Reactant: BrCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3cccnc3c2=O)cc1C
Reaction time: 0.08 h
Yield: 12.2 %

Procedure:
To a solution of 0.060 g (0.216 mmol) of 3-(3,4-Dimethyl-benzoyl)-1H-[1,5]naphthyridin-4-one in 2.0 mL of N,N-dimethylformamide was added 10.4 mg (0.259 mmol, 60% dispersion in oil) of sodium hydride and the reaction was stirred for 5 min. 65 mg (0.259 mmol) of 2-bromo-6-bromomethyl-pyridine was added and the reaction was stirred at room temperature for 3 h. Water was added and the solid collected by filtration. The crude brown solid was purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 11.8 mg of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-1H-[1,5]naphthyridin-4-one as an off white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][O:45][C:46]1[CH:47]=[C:48]([CH2:52][C:53](O)=[O:54])[CH:49]=[CH:50][CH:51]=1.CCN(C(C)C)C(C)C>O.CN(C)C=O>[CH3:44][O:45][C:46]1[CH:47]=[C:48]([CH2:52][C:53]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:14]5[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=5[S:12][CH:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:54])[CH:49]=[CH:50][CH:51]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: Nc1nccc2scc(-c3ccc4c(c3)CCN4)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(CC(=O)N2CCc3cc(-c4csc5ccnc(N)c45)ccc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
To a 4 mL screw cap vial was added 3-(2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (100 mg, 0.374 mmol) followed by HATU (142 mg, 0.374 mmol), 3-methoxyphenylacetic acid (62.2 mg, 0.374 mmol) and DIEA (0.261 mL, 1.496 mmol). N,N-Dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and left to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organics were dried over Na2SO4 and concentrated. The residue was taken up in DCM and purified via normal phase chromatography (0-10% MeOH/DCM). Fractions were collected and concentrated to afford 3-(1-{[3-(methyloxy)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (69.4 mg) as a white solid. LC/MS (ES) m/z=416.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 3.22 (t, J=8.34 Hz, 2H) 3.75 (s, 3H) 3.86 (s, 2H) 4.23 (t, J=8.46 Hz, 2H) 5.54 (br. s., 2H) 6.84 (dd, J=8.21, 2.40 Hz, 1H) 6.87-6.91 (m, 2H) 7.21-7.27 (m, 2H) 7.29 (d, J=5.56 Hz, 1H) 7.33 (s, 1H) 7.44 (s, 1H) 7.83 (d, J=5.81 Hz, 1H) 8.17 (d, J=8.34 Hz, 1H).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].Br[CH2:13][CH2:14][CH2:15][CH2:16]Br>CS(C)=O.C(OCC)(=O)C.CCCCCC>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:10]#[N:11])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrCCCCBr
Reactant: N#CCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#CC1(c2ccccn2)CCCC1
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
To a suspension of sodium hydride (60%) (0.745 g, 18.644 mmol) in dimethyl sulfoxide (10 mL) was dropwise added a mixture of pyridin-2-yl-acetonitrile (429) (1 g, 8.475 mmol) and 1,4-dibromo-butane (1.831 g, 8.475 mmol) dissolved in dimethyl sulfoxide-ether (10 mL, 1:1) at 0° C. and the reaction mixture was stirred for 30 min at the same temperature and then stirred at room temperature for 4 h. After completion of the reaction (monitored by silica TLC, Rf=0.4, in 10% ethyl acetate/hexane) the mixture was quenched with HCl (1N, 10 mL). The reaction mixture was diluted water (20 mL) and extracted with ethyl acetate (2×50 mL) combined extracts were washed with water (20 mL) and brine (2×20 mL). The organic phase was thereafter dried and concentrated in vacuo to get a crude mass which was purified by combi-flash to get 1-pyridin-2-yl-cyclopentanecarbonitrile (430) (1.2 g, 82%) as a color less liquid.