Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[NH:4][C:5]([CH3:9])([CH3:8])[C:6]#[CH:7].[F:11][C:12]1[C:13](I)=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])/[C:15]/2=[CH:22]\[C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28]>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.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3](=[O:10])[NH:4][C:5]([CH3:9])([CH3:8])[C:6]#[C:7][C:13]1[C:12]([F:11])=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:22]/[C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28])/[C:16](=[O:21])[NH:17]2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC(C)(C)NC(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C)(C)C#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, (1,1-dimethyl-2-propynyl)-carbamic acid methyl ester (47.7 mg, 0.34 mmol) (see below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 h to give
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[I:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:14][CH2:15][N:16]([C:24]([C:23]4[CH:27]=[CH:28][C:20]([I:19])=[CH:21][CH:22]=4)=[O:25])[CH2:17][CH2:18]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:2][CH2:3]1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: O=C(Cl)c1ccc(I)cc1
Product: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 90.9 %

Procedure:
Using 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (5.52 g) described in Preparation Example 88 and 4-iodobenzoyl chloride (6.35 g) and by the reaction and treatment in the same manner as in Preparation Example 114, the title compound (9.76 g) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[C:11]1([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:17]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:18]=[CH:19][C:20]([O:23][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)=[CH:21][CH:22]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(COc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A solution of alpha-bromo-p-tolunitrile (5.00 g, 25.5 mmol), 4-phenylphenol (4.56 g, 26.8 mmol), and potassium carbonate (10.6 g, 76.5 mmol) in N,N-dimethylformamide (75 mL) was stirred vigorously for 16 hours at room temperature. Water (75 mL) was added and the mixture was stirred at room temperature for 1 hour. The precipitate was filtered off and washed with thoroughly with water. Drying in vacuo over night at 50° C. afforded 7.09 g (97%) of 4-(biphenyl-4-yloxymethyl)benzonitrile as a solid.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[C:7]([CH3:20])[C:6]=2[CH:5]=[C:4]([CH3:21])[C:3]=1[CH3:22].N(S([O-])(=O)=O)(S([O-])(=O)=[O:26])[O].[K+].[K+]>CC(C)=O.OP([O-])(O)=O.[K+]>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:8]2[O:9][C:10]3[C:2](=[O:1])[C:3]([CH3:22])=[C:4]([CH3:21])[C:5](=[O:26])[C:6]=3[C:7]=2[CH3:20])=[CH:13][CH:14]=1
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Reactant: COc1ccc(Cc2oc3c(O)c(C)c(C)cc3c2C)cc1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Cc2oc3c(c2C)C(=O)C(C)=C(C)C3=O)cc1
Temperature: 45 °C

Procedure:
A solution of 7-hydroxy-2-(-4-methoxybenzyl)-3,5,6-trimethylbenzofuran from Step 4 (8.6 g, 29 mmol) in acetone (1.5 L) was added rapidly to a solution of potassium nitrosodisulfonate (Fremy's salt) (25 g, 93 mmol) in 0.055 M KH2PO4 buffer (1.5 L) at room temperature. The reaction was slowly heated to 45° C. over a period of 2 hr. The reaction was then cooled and the quinone was extracted with EtOAc (2x, 500 mL). Evaporation of the organic solvent gave a solid residue which was crystallized and re-crystallized from EtOH, to give the title compound, mp 111°-113° C.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:7][SiH:8]([Cl:10])[Cl:9]>[Pt]>[CH:1]1([Si:8]([CH3:7])([Cl:10])[Cl:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[SiH](Cl)Cl
Reactant: C1=CCCCC1
Agent: [Pt]
Product: C[Si](Cl)(Cl)C1CCCCC1
Reaction time: 70 h
Yield: 91 %

Procedure:
Into a glass-made flask of 100 ml capacity equipped with a reflux condenser and stirrer were introduced 0.25 mole of cyclohexene, 0.25 mole of methyl dichlorosilane and 0.11 g of the same platinum catalyst as used in Example 1 and the flask containing the mixture was put under direct sun light at room temperature. A reaction took place in the mixture and continued without loss of the catalyst activity. The reaction was almost complete after 70 hours of exposure to sun light. Distillation of the thus obtained reaction mixture gave cyclohexyl methyl dichlorosilane in a yield of 91%.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.[OH-].[Na+].C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:13])=[CH:6][C:7]=2[N:12]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1

Procedure:
Prepared analogously to Example 113a from 3,4-diamino-benzoic acid ethyl ester and 1,3-dichloro-2-isothiocyanato-benzene with DCC in DMF and NaOH in ethanol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([NH:11][C:12]3[C:13]4[CH2:21][NH:20][CH2:19][CH2:18][C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[CH:10][C:2]1=2.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([NH:11][C:12]3[C:13]4[CH2:21][N:20]([C:24]5[CH:23]=[C:22]([CH3:31])[CH:27]=[CH:26][CH:25]=5)[CH2:19][CH2:18][C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[CH:10][C:2]1=2
Reactant: Cc1cccc(B(O)O)c1
Reactant: c1nc2c(c(Nc3ccc4c(c3)OCCO4)n1)CNCC2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(N2CCc3ncnc(Nc4ccc5c(c4)OCCO5)c3C2)c1
Reaction time: 6 h
Yield: 9.6 %

Procedure:
5,6,7,8-Tetrahydro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrido[4,3-d]pyrimidin-4-amine (110 mg, 0.39 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added m-tolylboronic acid (105 mg, 0.78 mmol), Cu(OAc)2 (141 mg, 0.78 mmol) and triethylamine (0.68 g, 0.095 mL) and 390 mg of crushed, activated 4 A molecular seives. The mixture was agitated for 6 h and the solvent was removed under vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (14 mg, 9.6%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:19][NH2:20].C(N(CC)CC)C>C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:19][NH:20][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: COc1ccc(CN)cc1F
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
In DCM (50 mL) were dissolved ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1.5 g, 6.46 mmol), 3-fluoro-4-methoxybenzylamine (1.0 g, 6.45 mmol) and triethylamine (1.3 g, 12.9 mmol). The reaction mixture was stirred at ambient temperature for 30 min, and washed with water. The organic phase was dried over sodium sulfate and concentrated to give ethyl 4-((3-fluoro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylate as a yellow oil (2.2 g, yield: 97%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: Nc1ncccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ncccn1
Temperature: 25 °C

Procedure:
A solution of 2 amino-pyrimidine (2.0 g) in dry dichloromethane (17 mL) under nitrogen at 0° C. was treated with triethylamine (2.6 mL) followed by slow addition of chloroacetyl chloride (1.5 mL 18.4 mmol). The reaction mixture was allowed to warm up to room temperature. After 2h, the mixture was partitioned between dichioromethane and water.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl.Cl>COCCOCCOC.C(OCC)(=O)C>[ClH:12].[ClH:14].[C:1]([C:5]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=1[N:7]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(Cl)ccc1N
Reactant: ClCCNCCCl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COCCOCCOC
Product: CC(C)(C)c1cc(Cl)ccc1N1CCNCC1
Temperature: 170 °C
Reaction time: 72 h
Yield: 14.7 %

Procedure:
A mixture of 2-tert-butyl-4-chloroaniline (Reference Example 19, 16.7 g, 90.8 mmol) and bis(2-chloroethyl)amine hydrochloride (17.8 g, 99.9 mmol) in diglyme (170 mL) was stirred at 170° C. for 3 days under nitrogen atmosphere. After this time, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate and 1 M NaOH. The organic layer was washed with water, and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting brown oil was purified by flash column chromatography (NH-silica gel, 1:1-0:100 hexane/ethyl acetate, 10:1 ethyl acetate/MeOH) to provide an impure brown oil and a brown solid. The solid was dissolved in ethyl acetate and the solution was treated with 4 M HCl in ethyl acetate to give the title compound (2.17 g) as a brown solid. The impure brown oil was partitioned between ethyl acetate and 1 M HCl and the resulting white precipitate was collected by filtration, and washed with diethyl ether to give the title compound (2.98 g) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][S:20][C:16]=4[C:15](=[O:21])[N:14]([CH3:22])[CH2:13][C:12]=23)[O:6][CH:7]=1.[CH2:23]([NH:26][CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]>O1CCCC1>[CH2:23]([N:26]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][S:20][C:16]=4[C:15](=[O:21])[N:14]([CH3:22])[CH2:13][C:12]=23)[O:6][CH:7]=1)[CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25]
Reactant: CN1Cc2c(-c3nc(CCl)co3)ncn2-c2ccsc2C1=O
Reactant: CCCNCCC
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1coc(-c2ncn3c2CN(C)C(=O)c2sccc2-3)n1
Yield: 37.7 %

Procedure:
0.167 g (0.000498 mol) of 3-(4-chloromethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one was dissolved in 20 ml of tetrahydrofuran, treated with 1.4 ml (0.0102 mol) of dipropylamine and boiled at reflux for 20 hrs. The solution was completely freed from the solvents, the residue was chromatographed over silica gel with ethyl acetate/ethanol 1:1 as the eluent and recrystallized from diisopropyl ether. There was obtained 0.075 g (38%) of 3-(4-dipropylaminomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one as white crystals; m.p. 110-111°.
Reaction SMILES: CS(O[C@H:6]1[C:30]2[C@:25]([CH3:32])([CH2:26][CH2:27][C:28](=[O:31])[CH:29]=2)[C@@H:24]2[C@H:8]([C@H:9]3[C@:21]([CH3:33])([CH2:22][CH2:23]2)[C@@H:12]([C@H:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:11][CH2:10]3)[C@H:7]1OS(C)(=O)=O)(=O)=O.[N-:39]=[N+:40]=[N-:41].[Na+].C(O)(=O)C>CO>[N:39]([C:6]1[C:30]2[C@:25]([CH3:32])([CH2:26][CH2:27][C:28](=[O:31])[CH:29]=2)[C@@H:24]2[C@H:8]([C@H:9]3[C@:21]([CH3:33])([CH2:22][CH2:23]2)[C@@H:12]([C@H:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:11][CH2:10]3)[CH:7]=1)=[N+:40]=[N-:41]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@@H](OS(C)(=O)=O)[C@@H](OS(C)(=O)=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=C(N=[N+]=[N-])C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
In a manner similar to that described in Example 6C, treat 6β,7β-dimethanesulfonyloxy-4-cholestene-3-one with sodium azide in aqueous methanol in the presence of acetic acid. Isolate and purify the resultant product in a manner similar to that described to obtain 6-azido-4,6-cholestadiene-3-one.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1=[O:11])[CH2:2][CH2:3][CH3:4].N([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=C=O.C[N:22]([CH:24]=[O:25])C>>[CH2:1]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1=[O:11])[CH2:2][CH2:3][CH3:4].[CH2:15]([C:24]([NH2:22])=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCN=C=O
Reactant: CN(C)C=O
Agent: CCCCN1CC(=O)NC1=O
Product: CCCCCCC(N)=O

Procedure:
1-Butylimidazolidine-2,4-dione (100 mg, 0.64 mmol) and 1-isocyanatohexane (97.7 mg, 0.768 mmol) were reacted in DMF in analogy to example 1. Yield: 9 mg (5%), M+H+: 284.50.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:31][CH2:32][CH2:33][CH2:34]Cl)=[CH:24][C:25]=2[O:27][CH:28]([CH3:30])[CH3:29])[N:20]=[CH:19][N:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:55][N:56]1[CH2:61][CH2:60][NH:59][CH2:58][C:57]1=[O:62].[I-].[Na+]>COCCO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:31][CH2:32][CH2:33][CH2:34][N:59]3[CH2:60][CH2:61][N:56]([CH3:55])[C:57](=[O:62])[CH2:58]3)=[CH:24][C:25]=2[O:27][CH:28]([CH3:29])[CH3:30])[N:20]=[CH:19][N:18]=1
Reactant: CN1CCNCC1=O
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)cc(OC(C)C)c23)c2c1OCO2
Agent: [I-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: COCCO
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C)C(=O)C4)cc(OC(C)C)c23)c2c1OCO2
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-5-isopropoxyquinazolin-4-amine (0.320 g, as a 1:1.3 wt.:wt. mixture with triphenylphosphine) and 1-methylpiperazin-2-one (0.280 g) was dissolved in 2-methoxyethanol (7 ml), then sodium iodide (0.040 g) was added and the reaction mixture was then heated at 110° C. with stirring for 24 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (70 ml) and washed with water:brine (1:1) then water then brine and dried over magnesium sulfate before filtration and evaporation of solvents under reduced pressure. The residues so resulting were then purified by column chromatography on silica using increasingly polar mixtures of methanol in dichloromethane as eluent. There was thus obtained 4-(3-{4-[5-chloro-7-(3-methoxy-prop-1-ynyl)-benzo[1,3]dioxol-4-ylamino]-5-isopropoxy-quinazolin-7-yloxy}-propoxy)-1-methyl-piperazin-2-one (0.086 g) as a white foam; NMR Spectrum: (CDCl3) 1.53 (d, 6H), 2.02 (quin, 2H), 2.61 (t, 2H), 2.72 (t, 2H), 2.96 (s, 3H), 3.18 (s, 2H), 3.33 (t, 2H), 3.45 (s, 3H), 4.15 (t, 2H), 4.35 (s, 2H), 4.83 (sept, 1H), 6.10 (s, 2H), 6.49 (d, 1H), 6.82 (d, 1H), 7.05 (s, 1H), 8.51 (s, 1H), 9.41 (s, 1H); Mass Spectrum: M+H+ 596/598.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:20][C:8]=2[C:7]=1[OH:27])=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>C[O-].[Na+].CO>[OH:27][C:7]1[C:8]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:18][C:9]=2[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:11][C:6]=1[C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2nc(-c3ccccc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1nc(-c2ccccc2)c2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Yield: 96.6 %

Procedure:
A mixture of 7-hydroxy-2,4-diphenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (45 mg, 0.12 mmol) and glycine (179 mg, 2.38 mmol) in 0.5 M sodium methoxide/methanol (4.5 mL) was refluxed for four days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (20 mL) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (3 mL). The suspension was extracted with ethyl acetate (2×25 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (47 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.46 (t, 1H), 8.68 (m, 2H), 8.22 (m, 2H), 7.65 (m, 6H), 4.09 (m, 2H); MS: (+) m/z 406.0 (M+1)
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:19]([CH2:20][N:21]([C:24]([CH:26]3[CH2:28][CH2:27]3)=[O:25])[CH2:22][CH3:23])=[CH:18][C:17]([CH3:29])=[CH:16][N:15]=2)[CH:7]=1)C.[Li+].[OH-].CO>C1COCC1>[CH:26]1([C:24]([N:21]([CH2:20][C:19]2[C:14]([C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:30])=[O:3])[CH:11]=[CH:10][C:9]=3[O:12][CH3:13])=[N:15][CH:16]=[C:17]([CH3:29])[CH:18]=2)[CH2:22][CH3:23])=[O:25])[CH2:27][CH2:28]1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ncc(C)cc2CN(CC)C(=O)C2CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(Cc1cc(C)cnc1-c1cc(CC(=O)O)ccc1OC)C(=O)C1CC1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To (3-{3-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-5-methyl-pyridin-2-yl}-4-methoxy-phenyl)-acetic acid ethyl ester (0.154 g, 0.38 mmol) in THF (1.5 mL) was added 1N aqueous LiOH (1.14 mL, 1.14 mmol), and enough MeOH to clarify the solution. The reaction was stirred at 40° C. for 30 minutes, until no starting material was seen by analytical tlc. The mixture was concentrated, diluted with H2O, and washed twice with EtOAc. After filtering through a 25 μM nylon filter, the aqueous layer was acidified to pH 3 with 1N aqueous HCl, and the volume was reduced by half and then saturated with NH4Cl. The mixture was extracted five times with CH2Cl2, and then the aqueous layer was concentrated to leave residual salts and a trace of liquid, which was further extracted with CH2Cl2 until only a small amount of the desired product remained in the salts. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Br[C:13]1C=CC(C2CCCC2)=C[CH:14]=1.[Li]CCCC.CCCCCC.CN(C=O)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][CH:11]=2)[CH2:3][CH2:2][CH2:14][CH2:13]1
Reactant: Brc1ccc(C2CCCC2)cc1
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1ccc(C2CCCC2)cc1

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S1-A) using 2.07 g of 1-bromo-4-cyclopentyl-benzene (9.2 mmol), 6.32 ml of a 1.6 molar solution of n-BuLi in hexane (10.11 mmol) and 1.422 ml of DMF (18.4 mmol). 4-Cyclopentyl-benzaldehyde was isolated by flash column chromatography (5:95 EtOAc/c-hexane) as a colorless liquid (1146 mg, 72%). 1H NMR (CDCl3, 300 MHz): δ 1.53-1.91 (m, 6H), 2.11 (m, 2H), 3.07 (quint, J=8.5 Hz, 1H), 7.40 (d, J=8 Hz, 2H), 7.80 (d, J=8 Hz, 2H), 9.97 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[C:25]1[C:26]([N:45]2[CH2:49][C@H:48]([OH:50])[C@@H:47]([OH:51])[CH2:46]2)=[N:27][CH:28]=[C:29]([CH:44]=1)[C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]([Cl:43])([F:42])[F:41])=[CH:35][CH:34]=1)=[O:31]>CN(C=O)C.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>[Cl:43][C:40]([F:41])([F:42])[O:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:30]([C:29]2[CH:44]=[C:25]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])[C:26]([N:45]3[CH2:46][C@H:47]([OH:51])[C@@H:48]([OH:50])[CH2:49]3)=[N:27][CH:28]=2)=[O:31])=[CH:34][CH:35]=1
Reactant: CC1(C)OB(c2cnccc2C#N)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
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: CN(C)C=O
Product: N#Cc1ccncc1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1N1C[C@H](O)[C@@H](O)C1
Temperature: 130 °C
Reaction time: 0.25 h

Procedure:
4-Cyanopyridine-3-boronic acid pinacol ester (192 mg, 0.836 mmol), K2CO3 (0.418 mL, 0.836 mmol) and Pd(PPh3)4 (24.14 mg, 0.021 mmol) were added to a solution of 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)nicotinamide (Stage 248.1, 200 mg, 0.418 mmol) in DMF (2.5 mL) in a vial at RT. The vial was evacuated/purged with argon, sealed and heated at 130° C. for 18 h. The RM was diluted with EtOAc (60 mL) and washed with an aq. sat. solution of NaHCO3 (20 mL) and brine (2×20 mL). The organic phase was dried over Na2SO4, filtered and the solvent was evaporated off under reduced pressure. The resulting residue was suspended in MeOH (3 mL), stirred for at RT 15 min, filtered and washed with MeOH (2 mL). The filtrate was filtered through a SPE PL-Thiol cartridge (StratoSpheres™, 500 mg, nominal:1.5 mmol) and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column 2-EP, from 21% to 26% in 6 min) to afford the title product as a yellow solid. HPLC (Condition 10) tR=5.90 min, UPLC-MS (Condition 3) tR=0.94 min, m/z=502.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.95 (d, J=11.34 Hz, 2H) 3.14-3.39 (m, 2H) 3.86 (br. s, 2H) 5.02-5.07 (m, 1H) 5.09-5.14 (m, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.86 (d, J=8.60 Hz, 2H) 7.96-8.06 (m, 1H) 8.12 (d, J=17.60 Hz, 1H) 8.76-8.88 (m, 2H) 9.08 (br. s, 1H) 10.21 (d, J=4.69 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([NH2:23])=[O:22].[CH3:24][C:25]1[O:29][N:28]=[C:27]([CH2:30][NH2:31])[CH:26]=1>C(O)CCC>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:31][CH2:30][C:27]4[CH:26]=[C:25]([CH3:24])[O:29][N:28]=4)=[C:3]([C:21]([NH2:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: Cc1cc(CN)no1
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Solvent: CCCCO
Product: COc1cc2c(NCc3cc(C)on3)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Temperature: 110 °C

Procedure:
A solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 331 mg) and [(5-methyl-3-isoxazolyl)methyl]amine (2.5 eq) in butanol (20 ml) was heated to 110° C. for 4 h. The reaction mixture was evaporated to dryness and hydrolysed with water. The mixture was extracted with DCM and the organic dried over Na2SO4, filtered and concentrated to dryness (280 mg). Used without purification in the subsequent reaction (Example 52).