Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:25])(=O)C.[NH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1.N>ClCCl>[CH3:34][O:33][C:31]([C:30]1[CH:35]=[CH:36][C:27]([NH:26]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:28][CH:29]=1)=[O:32]
Reactant: COC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Agent: N
Solvent: ClCCl
Product: COC(=O)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 77 from 1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and methyl 4-aminobenzoate in dichloromethane and subsequent treatment with methanolic ammonia.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[O:11].[N+:24]([C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][C:36]=1[N:37]([CH2:39][CH:40]1[CH2:44][CH2:43][CH2:42][NH:41]1)[CH3:38])[C:30]([O:32][CH3:33])=[O:31])([O-:26])=[O:25]>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOCC.C1C=CC2N(O)N=NC=2C=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:41]2[CH2:42][CH2:43][CH2:44][CH:40]2[CH2:39][N:37]([C:36]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=2[N+:24]([O-:26])=[O:25])[CH3:38])=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[O:11]
Reactant: COC(=O)c1ccc(N(C)CC2CCCN2)c([N+](=O)[O-])c1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C)CC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3F)c(OC)c2)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 105.5 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-fluorophenyl)ureido]phenylacetic acid (630.0 mg, 1.979 mmol), methyl 3-nitro-4-[N-(2-pyrrolidinyl)methyl-N-methylamino]benzoate (553.0 mg, 1.885 mmol), EDC(Hydrochloride) (542.0 mg, 2.827 mmol), HOBt (25.5 mg, 0.189 mmol), and DMAP (23.1 mg, 0.189 mmol) in DMF (5.0 mL) was stirred at room temp. for 2 hr. The mixture was diluted with Et2O, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure, and the residue was chromatographed on silica-gel with CHCl3-MeOH (30:1, v/v) as eluent to afford 1.18 g (100%) methyl 4-[N-[1-[3-methoxy4-[N′-(2-fluorophenyl)ureido]phenylacetyl]-2-pyrrolidinyl methyl]-N-methylamino]-3-nitrobenzoate as a yellow foam, which is used to the subsequent reaction without further purification.
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[N:18][C:19]=3[O:28][CH3:29])[N:14]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5])=[N+]=[N-].[H][H]>CCO.[Pd]>[CH3:29][O:28][C:19]1[N:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[CH:21]=[C:22]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:4]([NH2:1])([CH3:6])[CH3:5])=[CH:12][CH:11]=1)=[N:14]2
Reactant: [H][H]
Reactant: COc1nccc2nc(-c3ccc(C(C)(C)N=[N+]=[N-])cc3)c(-c3cccs3)cc12
Agent: [Pd]
Solvent: CCO
Product: COc1nccc2nc(-c3ccc(C(C)(C)N)cc3)c(-c3cccs3)cc12

Procedure:
A mixture of 2-[4-(1-azido-1-methylethyl)phenyl]-5-methoxy-3-(2-thienyl)-1,6-naphthyridine (2-5, 78 mg, 0.194 mmol) and 10% Pd/C (9 mg) was stirred under 1atm hydrogen in EtOH (5 mL) for 2 h. The mixture was filtered through celite and concentrated to give the title compound as a clear oil. LRMS m/z (M+1) Calcd: 376.1,. Found 376.2.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:23])[CH2:20][CH2:21][CH3:22])=[N:18][C:12]=2[O:11][C@@H:10]([CH2:24][O:25][CH3:26])[CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:33]>CO.[OH-].[OH-].[Pd+2]>[ClH:33].[CH3:26][O:25][CH2:24][C@H:10]1[CH2:9][NH:8][CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:23])[CH2:20][CH2:21][CH3:22])=[N:18][C:12]=2[O:11]1
Reactant: CCCN(C)c1cnc2c(n1)O[C@@H](COC)CN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN(C)c1cnc2c(n1)O[C@@H](COC)CNC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of (6R)-8-benzyl-6-(methoxymethyl)-N-methyl-N-propyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (465 mg) in methanol (10 mL) was added 20% Pd(OH)2/C (50 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 3 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the obtained crude product in ethyl acetate (10 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (359 μL), and the mixture was stirred for 1 hr. The reaction mixture was filtered, and the obtained crystals were washed with ethyl acetate to give the title compound (223 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([S:13]([CH3:16])(=[O:15])=[O:14])S(C)(=O)=O)=[CH:6][C:5]([C:17]2[S:21][C:20](Cl)=[N:19][C:18]=2[CH3:23])=[CH:4][N:3]=1.[CH3:24][NH2:25]>C(O)C>[Cl:1][C:2]1[C:7]([NH:8][S:13]([CH3:16])(=[O:14])=[O:15])=[CH:6][C:5]([C:17]2[S:21][C:20]([NH:25][CH3:24])=[N:19][C:18]=2[CH3:23])=[CH:4][N:3]=1
Reactant: Cc1nc(Cl)sc1-c1cnc(Cl)c(N(S(C)(=O)=O)S(C)(=O)=O)c1
Reactant: CN
Solvent: CCO
Product: CNc1nc(C)c(-c2cnc(Cl)c(NS(C)(=O)=O)c2)s1
Temperature: 120 °C

Procedure:
A mixture of N-[2-chloro-5-(2-chloro-4-methyl-1,3-thiazol-5-yl)pyridin-3-yl]-N-(methylsulfonyl)methanesulfonamide (94 mg) and a 13% solution of methylamine in ethanol (5.0 mL) was stirred and heated to 120° C. in a sealed glass tube in a microwave reactor for 2.5 hours. The resultant mixture was evaporated. Ethanol was added and the mixture was re-evaporated. The material so obtained was purified by reversed phase preparative HPLC. There was thus obtained the title compound (25 mg); 1H NMR Spectrum: (DMSOd6) 2.23 (s, 3H), 2.83 (d, 3H), 3.13 (s, 3H), 7.76 (s, 1H), 7.82 (s, 1H), 8.23 (s, 1H), 9.77 (s, 1H); Mass Spectrum: M+H+ 333.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[N:7]=[CH:6][N:5]=1)[CH3:2].[C:19](OC(=O)C)(=[O:21])[CH3:20].[ClH:26]>C(OCC)(=O)C>[ClH:26].[CH2:17]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:19](=[O:21])[CH3:20])[CH:11]=2)[N:7]=[CH:6][N:5]=1)[CH3:18]
Reactant: CCN(CC)c1cc(-c2cccc(N)c2)ncn1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN(CC)c1cc(-c2cccc(NC(C)=O)c2)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5.6 g. (0.022 mole) of 4-diethylamino-6-(m-aminophenyl)pyrimidine is slowly added, with cooling, 25 ml. of acetic anhydride. The resulting solution is stirred overnight at room temperature and is then diluted with 500 ml. of ethyl acetate amd treated with sufficient gaseous hydrogen chloride to complete the precipitation of the desired product. The solvent and excess acetic anhydride are removed under reduced pressure and the residue washed from the flask with 20 ml. of 1:1 hexane/ethyl acetate 6.6 g., m.p. 235°-237° C. It proves to be identical to that prepared by the Acid Chloride Method.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=1.[I:10][C:11]1[N:12]=[C:13]([CH3:17])[NH:14][C:15]=1[CH3:16]>>[I:10][C:11]1[N:12]=[C:13]([CH3:17])[N:14]([C:2]2[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=2)[C:15]=1[CH3:16]
Reactant: Cn1ncc(Cl)cc1=O
Reactant: Cc1nc(I)c(C)[nH]1
Product: Cc1nc(I)c(C)n1-c1cnn(C)c(=O)c1

Procedure:
The title compound, light yellow cristalline solid, MS: m/e=331.0 (M+H+), was prepared in accordance with the general method of example 23b from 5-chloro-2-methyl-2H-pyridazin-3-one and 4-iodo-2,5-dimethyl-1H-imidazole.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][CH:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=1>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:39]=[CH:38][C:25]([O:26][CH:27]([C:28]([O:30][CH3:31])=[O:29])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:24][CH:23]=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2Cl)c(=O)[nH]1
Reactant: COC(=O)C(Oc1ccc(CBr)cc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48.2 %

Procedure:
A mixture of 64 mg (0.254 mmol) of the product of Step C, 6.1 mg (0.254 mmol) of sodium hydride, and 0.5 mL of DMF was stirred under N2 at room temperature for 2.5 hours. To this was then added 100 mg (0.299 mmol) of methyl 2-(4-bromomethylphenoxy)-2-phenylacetate (from Example 1, Step C), dissolved in a minimal amount of DMF. Stirring was continued for 48 hours. The mixture was then partitioned between 5 mL H2O and 8 mL EtOAc, and the aqueous layer was further extracted with 2×8 mL EtOAc. The combined organic layers were washed with 2×10 mL H2O and 1×10 mL brine, and dried over anhydrous Na2SO4. The filtrate was evaporated in vacuo, and the residue flash chromatographed over 40 mL silica gel (gradient elution with 0.5% to 2.0% methanol in CH2Cl2) to give 62 mg of the title compound as a colorless oil (48%), homogeneous by TLC in 50:1 CH2Cl2 --MeOH.
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:3]2[C:2]([N:22]3[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]3)=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:11][CH:12]=1
Reactant: OC1CCNCC1
Reactant: COc1ccc(COc2ncccc2Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(COc2ncccc2N2CCC(O)CC2)cc1
Temperature: 85 °C

Procedure:
A mixture of 3-bromo-2-(4-methoxybenzyloxy)pyridine (7.25 g, 24.65 mmol), 4-hydroxypiperidine (3.74 g, 36.97 mmol), tris(dibenzylideneacetone)dipalladium (451 mg, 0.493 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (614 mg, 0.986 mmol), and sodium-t-butoxide (3.32 g, 34.51 mmol) in anhydrous toluene (90 ml) was heated at 85° C. under nitrogen for 22 hours. The reaction mixture was diluted with ethyl acetate, washed with sat'd NaCl(aq.), dried (MgSO4), filtered, and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 1:1 hexanes: EtOAc to 3:7 hexanes: EtOAc) gave the title compound as a brown, viscous oil (4.45 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([OH:28])[CH2:27][CH2:26][N:25]([CH2:32][CH:29]5[CH2:31][CH2:30]5)[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=CC1CC1
Reactant: OC1(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: OC1(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2)CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 0.78 g (2.02 mmol) of 4-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenyl}piperidin-4-ol and 0.59 mL (8.06 mmol) of cyclopropanecarbaldehyde in 40 mL of THF was stirred for 30 minutes at RT, then combined with 1.71 g (8.06 mmol) of sodium triacetoxyborohydride and 0.46 mL (8.06 mmol) of glacial acetic acid and stirred for a further 2 days at RT. The reaction mixture was combined with DCM, and the organic phase was washed with semisaturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and evaporated down in vacuo. The crude product was stirred with isopropanol, and the precipitate was filtered off and dried in vacuo. Yield: 0.19 g (21% of theoretical); C28H27ClN2O (M=442.980); calc.: molpeak (M+H)+:443/445 (Cl); found: molpeak (M+H)+:443/445 (Cl); HPLC-MS: 7.26 minutes (method A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:31]([O:30][C:27]([C:24]1[CH:23]=[CH:22][C:21]([C:10]2[N:11]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]([CH3:14])[C:9]=2[S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:26][CH:25]=1)([CH3:28])[CH3:29])(=[O:33])[CH3:32]
Reactant: Cn1c(-c2ccccc2)nc(-c2ccc(C(C)(C)O)cc2)c1Sc1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OC(C)(C)c1ccc(-c2nc(-c3ccccc3)n(C)c2Sc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To 2-(4-{5-[(4-chlorophenyl)thio]-1-methyl-2-phenyl-1H-imidazol-4-yl}phenyl)propan-2-ol (Example 73, 300 mg, 0.69 mmol) in 4 mL of pyridine and 4 mL of acetic anhydride was added catalytic amount of DMAP. After stirring at 60° C. for 2 hr, the reaction was diluted with EtOAc, washed with water and brine, dried over MgSO4, filtered, and concentrated to dryness to afford 1-(4-{5-[(4-chlorophenyl)thio]-1-methyl-2-phenyl-1H-imidazol-4-yl}phenyl)-1-methylethyl acetate which was used in the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH:22][C:23](=[O:39])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[O:37][N:36]=[C:35]([CH3:38])[CH:34]=2)[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:38][C:35]1[CH:34]=[C:33]([C:29]2[CH:28]=[C:27]([C:25]3[CH2:24][C:23](=[O:39])[NH:22][C:9]4[CH:10]=[C:11]([C:20]#[N:21])[C:12]([N:14]5[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]5)=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[O:37][N:36]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N4CCCCC4)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N5CCCCC5)c(C#N)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (4-cyano-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-5-piperidin-1-yl-phenyl)-carbamic acid tert-butyl ester (Example M99) (0.41 g, 0.75 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (226 mg, 70%).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:28]1[CH2:31][CH:30]([OH:32])[CH2:29]1.C(N(CC)CC)C.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[OH:32][CH:30]1[CH2:31][N:28]([C:23]([C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8]3)(=[O:18])=[O:17])=[CH:27][CH:26]=2)=[O:25])[CH2:29]1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reactant: OC1CNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1)N1CC(O)C1
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
Dissolve 1-Benzhydryl-azetidin-3-ol (250 mg, 1.04 mmoL) in methanol (3.0 mL) and add to Pd(OH)2 (50 mg) under nitrogen. Degas reaction vessel and purge with 60 psi H2 (g). Repeat degass/H2 purge cycle again. Allow to stir under 60 psi H2 for 15 h. Release reaction and filter through celite with additional methanol. Evaporate methanol to yield azetidin-3-ol as a liquid which is used without further purification. Combine 4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid (200 mg, 0.53 mmol) and azetidin-3-ol (50 mg, 0.68 mmol, excess) in dichloromethane (1.0 mL) and triethylamine (0.500 mL, 3.58 mmol, excess) and add benzotriazol-1-yloxytris(dimethylamino)phosphonium hexfluorophosphate (BOP Reagent) (300 mg, 0.66 mmol, excess) at room temperature. Stir for 30 minutes, load entire reaction directly onto pre-packed silica gel column and purify by flash column chromatography (EtOAc/Hexanes) to yield 167 mg of (3-Hydroxy-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone as a white foam (73%). LRMS: MH+ 432.97.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:40][C:37]1[CH:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:41])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:23])[F:21])[C:12]([N:14]5[CH2:15][CH2:16][S:17][CH2:18][CH2:19]5)=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[O:39][N:38]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCSCC4)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N5CCSCC5)c(C(F)(F)F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-5-thiomorpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example M25) (310 mg, 0.5 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (80 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[H][H]>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:14]=[CH:15][C:16]=1[NH2:17]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OCCN2CCOCC2)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(OCCN2CCOCC2)cc1F
Yield: 93.5 %

Procedure:
A mixture of 4-[2-(3-fluoro-4-nitro-phenoxy)-ethyl]-morpholine (2.4 g, 8.9 mmol) and 5% Pd—C (0.3 g) in ethyl acetate (70 mL) was shaken under 50 psi of hydrogen for 20 hours. The mixture was filtered through Celite and evaporated, providing 2.0 g of the product, in 94% yield; 1H NMR (DMSO-d6) δ 2.44 (t, J=4.5, 4H), 2.62 (t, J=5.8 Hz, 2H), 3.57 (t, J=4.5, 4H), 3.95 (t, J=5.8 Hz, 2H), 6.50-6.55 (m, 1H), 6.52-6.72 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[CH:16]([C:18]1[CH:19]=[CH:20][C:21]([OH:27])=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24])=[O:17]>CN(C)C=O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][O:27][C:21]2[CH:20]=[CH:19][C:18]([CH:16]=[O:17])=[CH:26][C:22]=2[C:23]([O:25][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:24])=[CH:10][CH:11]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)OCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cesium carbonate (11.77 g, 36.1 mmol) and 1-(bromomethyl)-4-fluorobenzene (1.50 ml, 12.04 mmol) were added to a solution of 5-formyl-2-hydroxybenzoic acid (2 g, 12.04 mmol) in dimethylformamide (100 m) at room temperature. The mixture was stirred at room temperature overnight. The mixture was filtered, the dimethylformamide was evaporated and the residue was diluted with ethyl acetate (100 ml) and washed with water (3×50 ml). The organic layer was dried (MgSO4) and evaporated under reduced pressure to give an oil which solidified on standing. The solid was triturated with an 8:1 mixture of hexane/ethyl acetate. The solid was filtered and dried in air under vacuum to yield the title compound as a white solid. 4.09 g.
Reaction SMILES: CN(C)CC(N1C2C(=CC(OC)=C(NC3N4C(=NC5C(C4=O)=C(F)C=C(F)C=5)C4C=CN(S(C5C=CC(C)=CC=5)(=O)=O)C=4N=3)C=2)CC1)=O.CC(N)CC.[CH3:54][N:55]([CH3:106])[CH2:56][C:57]([N:59]1[C:67]2[C:62](=[CH:63][C:64]([O:104][CH3:105])=[C:65]([NH:68][C:69]3[N:70]=[C:71]([NH:88][C:89]4[CH:101]=[C:100]([F:102])[CH:99]=[C:98]([F:103])[C:90]=4[C:91]([NH:93][CH2:94][CH:95]([CH3:97])[CH3:96])=[O:92])[C:72]4[CH:77]=[CH:76][N:75](S(C5C=CC(C)=CC=5)(=O)=O)[C:73]=4[N:74]=3)[CH:66]=2)[CH2:61][CH2:60]1)=[O:58].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C.O1CCOCC1>[CH3:106][N:55]([CH3:54])[CH2:56][C:57]([N:59]1[C:67]2[C:62](=[CH:63][C:64]([O:104][CH3:105])=[C:65]([NH:68][C:69]3[NH:74][C:73]4=[N:75][CH:76]=[CH:77][C:72]4=[C:71]([NH:88][C:89]4[CH:101]=[C:100]([F:102])[CH:99]=[C:98]([F:103])[C:90]=4[C:91]([NH:93][CH2:94][CH:95]([CH3:97])[CH3:96])=[O:92])[N:70]=3)[CH:66]=2)[CH2:61][CH2:60]1)=[O:58]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cc(F)cc(F)c3C(=O)NCC(C)C)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Agent: CCC(C)N
Agent: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4cc(F)cc(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Nc1nc(Nc3cc(F)cc(F)c3C(=O)NCC(C)C)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,10-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (300 mg, 0.445 mmol) in THF (5 mL) was added methyl-1-propanamine (0.22 mL, 2.22 mmol). The resulting mixture was let stir at rt for 6 h at which time it was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a yellow solid, containing 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluoro-N-(2-methylpropyl)benzamide. This crude material was dissolved in 1,4-dioxane (5 mL) and transferred to a 20 ml microwave vessel. A solution of 2 M NaOH (5 ml) was added and reaction heated in microwave at 120° C. for 8 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a yellow solid which was purified via chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4,6-difluoro-N-(2-methylpropyl)benzamide (50 mg, 0.084 mmol) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.69 Hz, 6 H) 1.84 (dt, J=13.40, 6.72 Hz, 1 H), 2.24 (s, 6 H), 3.07-3.20 (m, 6 H), 3.76 (s, 3H), 4.16 (t, J=8.34 Hz, 2 H), 6.21 (dd, J=3.21, 1.65 Hz, 1 H), 6.79-6.93 (m, 1 H), 6.93-7.01 (m, 2 H), 7.79 (s, 1 H), 8.39-8.47 (m, 1 H), 8.50 (s, 1 H), 8.63-8.74 (m, 1 H), 10.32 (s, 1 H), 11.32 (br. s., 1 H). (ESIMS (M+H)+=593)