Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CC(C)([O-])C.[K+].[O:17]1[CH2:20][CH2:19][C:18]1=[O:21]>C1COCC1>[Br:1][C:2]1[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH2:20][CH2:19][C:18]([OH:21])=[O:17]
Reactant: O=Cc1cccc(O)c1Br
Reactant: O=C1CCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=Cc1cccc(OCCC(=O)O)c1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromo-3-hydroxybenzaldehyde (1 eq.) in THF (1.2 M) was added sequentially potassium tert-butoxide (1.0 M THF solution, 0.8 eq.) and oxetan-2one at RT. The resulting yellow suspension was stirred at RT for 16 h. The reaction mixture was quenched with 10% aq. HCl and extracted with EtOAc. The combined organic extracts were washed with water and brine. Drying over MgSO4, filtration and concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: O[NH:2][N:3]=[CH:4][N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13](=[O:34])[C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:33])[C@@H:20]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:7][CH2:6]1.[N-:35](C#N)[C:36]#N.[Na+]>CCCCO>[C:36]([NH:2][N:3]=[CH:4][N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13](=[O:34])[C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:33])[C@@H:20]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:7][CH2:6]1)#[N:35]
Reactant: N#C[N-]C#N
Reactant: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCC1CCN(C=NNO)CC1
Agent: [Na+]
Solvent: CCCCO
Product: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCC1CCN(C=NNC#N)CC1
Yield: 57 %

Procedure:
To a stirred solution of Example 3 Part D compound (220 mg, 0.40 mmol) in 3.0 mL of n-BuOH was added sodium dicyanamide (99.0 mg, 1.00 mmol). The reaction mixture was heated to reflux for 14 h and concentrated in vacuo. This was purified by preparative HPLC to give 124 mg (57%) of title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([OH:21])=O)=[CH:11]2)[C:4]=1[CH3:22].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(N(CC)CC)C.[CH:48]1([CH2:51][NH2:52])[CH2:50][CH2:49]1>C(Cl)Cl.O>[CH:48]1([CH2:51][NH:52][C:19]([C:12]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:18]3[N:10]([CH2:9][C:5]3[C:4]([CH3:22])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=3)[CH:11]=2)=[O:21])[CH2:50][CH2:49]1
Reactant: NCC1CC1
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncccc32)c1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncnc(Cn2cc(C(=O)NCC3CC3)c3ncccc32)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
See FIG. 16(b). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (200 mg, 0.67 mmol) was taken in DCM (10 mL). Added 1-Propanephosphonic acid cyclic anhydride (427 mg, 1.34 mmol) followed by the addition of Triethyl amine (339 mg, 3.35 mmol) and cyclopropylmethanamine (95 mg, 1.34 mmol). The reaction mass was stirred at RT for overnight. After the completion of the reaction added water and extracted with DCM. The organic layer was washed with water and brine solution. The organic layer was separated, dried over sodium sulphate. Evaporated the organic layer to get the residue, which was purified by column chromatography to get the pure compound. Yield-74%. ES+MS m/z: 352.38 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.02 (q, J=4.58 Hz, 2 H ) 0.18-0.31 (m, 2 H ) 0.83 (t, J=6.88 Hz, 1 H ) 2.00 (s, 3 H ) 2.98-3.11 (m, 3 H ) 3.69 (s, 3 H ) 5.43 (s, 2 H ) 7.00 (dd, J=8.29, 4.71 Hz, 1 H ) 7.68 (dd, J=8.29, 1.13 Hz, 1 H ) 7.98 (s, 1 H ) 8.17 (s, 1 H) 8.24 (dd, J=4.71, 1.13 Hz, 1 H ) 8.55 (t, J=5.75 Hz, 1 H ).
Reaction SMILES: Cl[C:2]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([OH:11])[CH2:9][OH:10])=[O:5].[NH:22]1[CH2:24][CH2:23]1>CCOC(C)=O>[N:22]1([C:2]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[CH:12][C:3]=2[C:4]([NH:6][CH2:7][CH:8]([OH:11])[CH2:9][OH:10])=[O:5])[CH2:24][CH2:23]1
Reactant: O=C(NCC(O)CO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reactant: C1CN1
Solvent: CCOC(C)=O
Product: O=C(NCC(O)CO)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1N1CC1
Yield: 44.4 %

Procedure:
A stirred solution of 2-chloro-N-(2,3-dihydroxypropyl)-3,5-dinitrobenzamide (Palmer et al., J. Med. Chem. 1996, 39, 2518-2528) (670 mg, 2.10 mmol) in EtOAc (35 mL) was treated with aziridine (325 μL, 6 28 mmol) at room temperature for 3 h, then concentrated under reduced pressure. The residue was dissolved in warm EtOAc (220 mL) and filtered though a short column of silica gel to give 17 (304 mg, 44%). mp (EtOAc/petroleum ether) 154-155° C., 1NMR [(CD3)2SO] δ8.74 (d, J=2.7 Hz, 1H, H-4), 8.57 (t, J=5 6 Hz, 1H, NH), 8.36 (d, J=2.7 Hz, 1 H, H-6), 4 88 (d, J=5.3 Hz, 1H, CHOH), 4.64 (t, J=5.7 Hz, 1H, CH2OH), 3 73-3 63 (m, 1H, CHOH), 3.52-3.42 (m, 1H, NHCHH), 3.42-3.34 (m, 2H, CH2OH), 3.26-3.15 (m, 1H, NHCHH), 2.39 (s, 4H, aziridine-H). Anal. Calcd for C12H14N4O7. C, 44.2;H, 4.3, N, 17.2. Found: C, 44.3;H, 4.2, N, 17.3%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[O:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:33]=[C:32]([NH:34][C:35](=O)[O:36]C3C=CC=CC=3)[O:31][N:30]=2)[CH2:25][CH2:24]1.COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:35]([NH:34][C:32]2[O:31][N:30]=[C:29]([CH:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[CH:33]=2)=[O:36])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C2CCOCC2)no1)Oc1ccccc1
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5CCOCC5)no4)c3)c2cc1OC
Yield: 46.1 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3 mmol) was reacted with phenyl 3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-ylcarbamate (104 mg, 0.36 mmol) according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-yl)urea as a cream solid (68 mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ 10.25 (brs, 1H), 9.07 (s, 1H), 8.56 (s, 1H), 7.56-7.58 (m, 2H), 7.39-7.44 (m, 2H), 7.31 (m, 1H), 6.99 (m, 1H), 6.01 (s, 1H), 3.99-4.00 (2×s, 6H), 3.86-3.90 (m, 2H), 3.40-3.46 (m, 2H), 2.90 (m, 1H), 1.69-1.76 (m, 2H), 1.60-1.69 (m, 2H); LC-MS (ESI) m/z 492 (M+H)+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[C:27]2[NH:34]N>>[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[C:27]2[N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: COc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Reactant: NNc1ccnc2ccc(F)cc12
Product: COc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccnc4ccc(F)cc34)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methoxy-phenyl)-1H-pyridazin-4-one (A-5) and (6-fluoro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=414.3 (M+H)+
Reaction SMILES: Cl[CH2:2][C:3]1[CH:35]=[CH:34][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([NH:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[N:19]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:2][C:3]2[CH:35]=[CH:34][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([NH:17][C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([C:28]5[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=5)[N:19]=4)[CH:11]=3)=[O:8])=[CH:5][CH:4]=2)[CH2:39][CH2:38]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Temperature: 25 °C
Yield: 41 %

Procedure:
To a stirring mixture of 4-chloromethyl-N-[4-methyl-3-(2-pyridin-4-yl-6-(trifluoromethyl)pyrimidin-4-ylamino)-phenyl]benzamide (48 mg, 0.096 mmol) and 1-methylpiperazine (16 pl, 0.0.144 mmol) in anhydrous tetrahydrofuran (5 ml) was added N,N-diisopropylethylamine (200 μl). The mixture was refluxed for 20 h. The mixture was cooled to room temperature and then rotary evaporated to dryness. The residue was purified by column chromatography and isolated as a tan solid (22 mg, 41%). 1H NMR (CDCl3): 8.77 (dd, J=1.8, 4.5 Hz, 2H), 8.29 (dd, J=1.5, 4.5 Hz, 2H), 8.01 (s, 1H), 7.85 (s, 1H), 7.83 (d, J=8.1 Hz, 2H), 7.47 (d, J=1.8 Hz, 2H), 7.37 (dd, J=1.5, 8.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.04 (s, 1H), 6.74 (s, 1H), 3.57 (s, 2H), 2.47 (s, 8H), 2.29 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][OH:20])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1>CO.O=[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][OH:20])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: OCC#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1
Agent: O=[Pt]=O
Solvent: CO
Product: OCCCc1ccc2c(ccn2-c2ccc(F)cc2)c1
Yield: 87.9 %

Procedure:
800 mg (3 mmol) 3-[1-(4-Fluoro-phenyl)-1H-indol-5-yl]-prop-2-yn-1-ol in 25 ml MeOH were hydrogenated in the presence of 100 mg PtO2, filtered and evaporated to yield 710 mg crude 3-[1-(4-Fluoro-phenyl)-1H-indol-5-yl]-propan-1-ol as colorless gum, MS: 270 (MH+).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9](=[O:15])[NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:4].[Li+].[OH-].Cl>CO.O>[C:11]([NH:10][C:9]([N:6]1[CH2:7][CH2:8][C@H:5]1[C:3]([OH:4])=[O:2])=[O:15])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)[C@@H]1CCN1C(=O)NC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)NC(=O)N1CC[C@H]1C(=O)O
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of (2S)-methyl-1-(N-t-butylcarbamoyl)azetidine-2-carboxylate from Reference Example 5 (211.6 mg, 0.99 mmol) in methanol (5.0 mL) was added 1N LiOH in water (1.8 mL) at about 0° C. The mixture was warmed to about room temperature and stirred under argon overnight. The pH was adjusted to about pH 1 by adding 1N HCl and then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give 211.3 mg (85% yield) of the product as a yellow oil. 1H NMR (CDCl3) δ 1.38 (s, 9H); 2.34-2.46 (m, 1H); 2.61-2.74 (m, 1H) 3.71-3.88 (m, 2H); 4.18-4.26 (br, 1H); 4.82 (t, 1H, J=8.6).
Reaction SMILES: O.[NH2:2]N.C[N:5](C)/[CH:6]=[CH:7]/[C:8]([C:10]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:17][C:16]2[CH2:26][NH:27][CH2:28][C:29](=[O:30])[N:14]3[C:15]=2[C:11]=1[CH:12]=[CH:13]3)=O>C1COCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[C:10]([C:8]3[NH:2][N:5]=[CH:6][CH:7]=3)=[C:11]3[C:15]4=[C:16]([CH2:26][NH:27][CH2:28][C:29](=[O:30])[N:14]4[CH:13]=[CH:12]3)[CH:17]=2)=[CH:24][CH:23]=1
Reactant: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)cc2c3c1ccn3C(=O)CNC2
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: O=C1CNCc2cc(-c3ccc(F)cc3)c(-c3ccn[nH]3)c3ccn1c23
Reaction time: 42 h
Yield: 22.5 %

Procedure:
Hydrazine monohydrate (5.14 mmol, 0.26 mL) was added to a solution of 7-[(E)-3-Dimethylamino-allanoyl]-6-(4-fluoro-phenyl)-3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-one (Example 159) (0.257 mmol, 0.097 g) in 10 mL THF at rt. The reaction mixture was stirred for 42 h. The reaction mixture was evaporated to dryness. The residue was taken up in 2N HCl and extracted with EtOAc several times. The combined organic layers was dried over anhydrous MgSO4 and concentrated to give a yellow oil which was purified by flash silica gel chromatography eluting with a gradient of 0-3% MeOH in CHCl3 to give 0.020 g (23%) of a yellow solid: mp=173-175° C.; 1H NMR (DMSO-d6) δ 3.45-3.52 (m, 2H), 4.03-4.08 (m, 2H), 5.64 (br s, 1H), 7.23 (t, 1H, J=6.0 Hz), 7.32 (t, 2H, J=9.0 Hz), 7.38-7.55 (m, 3), 7.88 (d, 1H, J=6.0 Hz), 8.36-8.43 (m, 2H), 12.67 (br s, 1H); HRMS calcd. for C20H15N4OF (M+) 346.1221, found (M+) 346.1225; Anal. for (C20H15N4OF.1.0MeOH) C, H, N.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:16][C:17]1[NH:21][C:20]2[C:22](=O)[CH2:23][CH2:24][C:19]=2[C:18]=1[C:26]([OH:28])=[O:27]>CN(C=O)C.N1CCCCC1>[CH3:16][C:17]1[NH:21][C:20]2/[C:22](=[C:9]3\[C:10](=[O:15])[NH:11][C:12]4[C:8]\3=[CH:7][C:6]([S:3](=[O:5])(=[O:4])[NH:2][CH3:1])=[CH:14][CH:13]=4)/[CH2:23][CH2:24][C:19]=2[C:18]=1[C:26]([OH:28])=[O:27]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: Cc1[nH]c2c(c1C(=O)O)CCC2=O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C1\CCc3c1[nH]c(C)c3C(=O)O)C(=O)N2
Temperature: 110 °C
Reaction time: 48 h
Yield: 24.5 %

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (905 mg, 4 mmol) and 2-methyl-6-oxo-1,4,5,6-tetrahydro-cyclopenta[b]pyrrole-3-carboxylic acid (Example B, 716 mg, 4 mmol) in DMF (50 mL) and piperidine (5 mL) was heated at 110° C. with stirring for 48 hours. The solvent was removed and the residue was suspended in methanol-ice-water and acidified with 2N HCl. The solid was collected by filtration and then suspended in DCM. The suspension was washed with 2N aq. NaOH for three times. The combined water layer was backwashed with DCM. The water layer was acidified with 2N HCl and filtered to give a brown solid, which was triturated with MeOH to afford 380 mg of the titled compound as a brown yellow solid. The combined organic layer was dried (Na2SO4) and evaporated to give 130 mg of 3-[2-methyl-4,5-dihydro-1H-cyclopenta[b]pyrrol-(6Z)-ylidene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (Example 4) as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6]O)[CH3:2].[NH2:10][C:11]([NH2:13])=[S:12].[BrH:14]>>[BrH:14].[BrH:14].[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][S:12][C:11](=[NH:10])[NH2:13])[CH3:2]
Reactant: CCN(CC)CCCO
Reactant: NC(N)=S
Agent: Br
Product: CCN(CC)CCCSC(=N)N

Procedure:
A mixture of 3-(diethylamino)propyl alcohol (65.5 g), thiourea (38.0 g) and aqueous hydrobromic acid (48%, 25 ml) was boiled under reflux for 17 hours, and evaporated to dryness. The residue was triturated with ethanol and recrystallised from ethanol/methanol to give the title product, m.p. 125°-127° which was further recrystallised from absolute ethanol to give a 10.0 g sample with m.p. 144°-145°.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][C:7]([Br:10])=[CH:8][CH:9]=1)=[O:4].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:2][C:3]([C:5]2[S:6][C:7]([Br:10])=[CH:8][CH:9]=2)=[O:4])=[CH:14][CH:13]=1
Reactant: O=C(CBr)c1ccc(Br)s1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(COc1ccc(Cl)cc1)c1ccc(Br)s1
Yield: 52.2 %

Procedure:
28.4 g (0.1 mol) of 2-bromoacetyl-5-bromothiophene are heated under reflux with 19.3 g (0.15 mol) of 4-chlorophenol and 27.6 g (0.2 mol) of potassium carbonate in 200 ml of ketone for 3 hours, while stirring. The mixture is then poured into water, and the ether-ketone is extracted with methylene chloride. The organic phase is washed with dilute sodium hydroxide solution and then with water, and is dried over magnesium sulphate. After the organic phase has been evaporated down, the residue is recrystallized from ethanol. 17.3 g (52% of theory) of 2-bromo-thien-5-yl 4-chlorophenoxymethyl ketone of melting point 128°-130° C. are obtained.
Reaction SMILES: N12CCCN=C1CCCCC2.[N:12]1([CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25]([C:30]2[C:38]4[C:33](=[CH:34][CH:35]=[C:36](O)[CH:37]=4)[NH:32][N:31]=2)=[CH:24]3)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[N+](C1C=C[C:46]([O:49][P:50](C)(=[O:61])[O:51]C2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O.C(=O)(O)[O-].[Na+]>ClCCl.CO>[CH3:46][O:49][P:50]([C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[C:30]2[C:25]1[NH:26][C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:20][CH2:19][CH2:18][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[CH:29][CH:28]=2)(=[O:51])[OH:61]
Reactant: CP(=O)(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: Oc1ccc2[nH]nc(-c3cc4cc(OCCN5CCCCC5)ccc4[nH]3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: COP(=O)(O)c1ccc2[nH]nc(-c3cc4cc(OCCN5CCCCC5)ccc4[nH]3)c2c1
Reaction time: 16 h
Yield: 38.2 %

Procedure:
77 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene are added to a solution of 193 mg of 3-[5-(2-piperidin-1-ylethoxy)-1H-indol-2-yl]-1H-indazol-5-ol and 173.5 mg of methylphosphonic acid bis-(4-nitrophenyl) ester in 10 ml of dichloromethane and the mixture is allowed to react at 20° C. After reaction for three hours, 300 μl of methanol and then 77 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene are added and the reaction is continued at 20° C. for 16 hours. The reaction medium is then taken up in a mixture of dichloromethane (150 ml) and a saturated sodium bicarbonate solution (100 ml). After separation by settling out and extraction with dichloromethane (50 ml), the organic extracts are combined, dried over magnesium sulfate and then evaporated under reduced pressure. The crude compound thus obtained is purified by chromatography on silica (Interchrom column, reference DC0210, 20 g silica, eluent dichloromethane/methanol 9/1 v/v, 15 ml/min). The fractions containing the expected compound are combined and evaporated under reduced pressure. 89 mg of 3-[5-(2-piperidin-1-ylethoxy)-1H-indol-2-yl]-1H-indazol-5-ylphosphonic acid methyl ester are isolated and characterized.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:16])[CH:15]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:16])[C:15]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)Cl
Reactant: Brc1cncc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Br)cncc1Br
Reaction time: 0.75 h
Yield: 91.7 %

Procedure:
To a solution of LDA (2 M solution in THF/heptane/ethylbenzene) (2.26 g, 10.54 mL, 21.06 mmol) in anhydrous THF (20 mL) under nitrogen atmosphere cooled to −78° C. was added a solution of the 3,5-dibromopyridine (5.0 g, 21.10 mmol) in anhydrous THF (40 mL) at −78° C. The reaction mixture was allowed to stir at the same temperature for 45 minutes. Then, a solution of chloro(ethoxy)methanone (22.90 g, 211.02 mmol) was added slowly over 15 minutes. After stirring for 20 minutes, the reaction mixture was quenched with saturated aqueous NaHCO3. The mixture was extracted with ethyl acetate (3×100 mL), and the combined organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated, and the residue was purified through CombiFlash using 0-10% ethyl acetate in hexane to provide ethyl 3,5-dibromopyridine-4-carboxylate as pale yellow oil (5.98 g, 92% yield); 1H NMR (400 MHz, DMSO-d6): δ1.43 (t, 3H), 4.49 (q, 2H), 8.67 (s, 2H); M+307.9.
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[C@H:2]([C:6](ON1C(=O)CCC1=O)=[O:7])[CH:3]([CH3:5])[CH3:4].[NH2:33][C@H:34]([C:54]([OH:56])=[O:55])[CH2:35][CH2:36][CH2:37][CH2:38][NH:39][S:40]([C:43]1[C:52]([CH3:53])=[C:50]([CH3:51])[C:47]([O:48][CH3:49])=[CH:46][C:44]=1[CH3:45])(=[O:42])=[O:41]>>[NH:1]([C:16]([O:18][CH2:19][CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[C:32]1=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17])[C@H:2]([C:6]([NH:33][C@H:34]([C:54]([OH:56])=[O:55])[CH2:35][CH2:36][CH2:37][CH2:38][NH:39][S:40]([C:43]1[C:52]([CH3:53])=[C:50]([CH3:51])[C:47]([O:48][CH3:49])=[CH:46][C:44]=1[CH3:45])(=[O:42])=[O:41])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](N)C(=O)O)c(C)c1C
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)ON1C(=O)CCC1=O
Product: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](NC(=O)[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(C)C)C(=O)O)c(C)c1C

Procedure:
This was prepared from Fmoc-Val-OSu 7b (20.7 mmol) and Lys(Mtr) 2 (9.09 g, 1.05 equiv) as described above for 8a (15.28 g, 100%). 1H-NMR (CDCl3/CD3OD) δ 0.85 (m, 6H), 1.20 (m, 2H), 1.59 (m, 4H), 1.99 (m, 1H), 2.41 (m, 2H), 3.71 (s, 3H), 4.21 (m, 5H), 6.78 (d, 2H), 7.29 (m, 16H), 7.51 (brt, 2H), 7.71 (d, 2H). MS (FAB) 740 (MH)+, 762 (M+Na)+. HRMS Calcd: 740.3700. Found: 740.3712.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=O)[O:5][C:6]=1[CH3:7].[NH3:16]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:16][C:6]=1[CH3:7]
Reactant: N
Reactant: Cc1cc(C(=O)c2ccccn2)oc1C
Solvent: CO
Product: Cc1cc(O)c(-c2ccccn2)nc1C
Temperature: 160 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(2-pyridyl)-methanone (1.6 g), methanol (15 ml), and a 28% aqueous ammonia solution (15 ml) were placed in a sealed tube, and the mixture was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give 5,6-dimethyl-[2,2′]-bipyridin-3-ol (1.2 g, yield 75%).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][C:9](=O)[CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3][CH2:2]1.[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[N:13].C([O-])(=O)C.[NH4+].C(O)(=O)C>O.C1C=CC=CC=1>[C:12](/[C:14](=[C:9]1\[CH2:8][CH2:7][O:6][C:5]2([CH2:10]\1)[CH2:4][CH2:3][CH2:2][CH2:1]2)/[C:15]([O:17][CH3:18])=[O:16])#[N:13]
Reactant: O=C1CCOC2(CCCC2)C1
Reactant: COC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)/C(C#N)=C1/CCOC2(CCCC2)C1

Procedure:
A 100 ml round-bottom flask equipped with a Dean-Stark distillation setup and condenser was charged with 6-oxaspiro[4.5]decan-9-one (6 g, 39 mmol, which was prepared according to Hanschke, E. Chem. Ber. 1955, 88, 1053), methyl cyanoacetate (4.1 ml, 46.7 mmol), ammonium acetate (780 mg, 10.1 mmol), acetic acid (0.44 ml, 7.8 mmol) and benzene (40 ml). The mixture was refluxed until no more water collected in the Dean-Stark (2 hours), cooled, benzene (30 ml) added and the organic washed with water (50 ml). The aqueous layer was extracted with CH2Cl2 (3×50 ml). The combined organic phase was washed with sat. NaHCO3 (100 ml), brine (100 ml) dried (MgSO4), filtered and concentrated. Purified by normal phase SiO2 chromatography (7% to 60% EtOAc/hexanes) to give methyl 2-cyano-2-[(9Z)-6-oxaspiro[4.5]decan-9-ylidene]acetate as a colorless oil (8.93 g, 97.5%, m/z 235.1 [M+H]+ observed).
Reaction SMILES: [CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>>[CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[N:8]2[C:17]([C:16]2[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:15]=2[CH3:14])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)NN(C2CCCCC2)C1=O
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Product: Cc1ccc(C(=O)N2N(C3CCCCC3)C(=O)C2(C)C)c(C)c1

Procedure:
2-Cyclohexyl-4,4-dimethyl-1,2-diazetidin-3-one and 2,4-dimethylbenzoyl chloride were used for a similar reaction and treatment as Example 96, and the title compound was obtained as a colorless oil.