Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(O)(=O)C.[O-:26][C:27]#[N:28].[Na+]>O>[NH2:14][C:11]1[N:10]=[C:9]([NH2:15])[C:8]([O:7][C:6]2[C:5]([CH:17]([CH3:19])[CH3:18])=[CH:4][C:3]([O:20][CH3:21])=[C:2]([NH:1][C:27]([NH2:28])=[O:26])[CH:16]=2)=[CH:13][N:12]=1
Reactant: N#C[O-]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1NC(N)=O
Reaction time: 0.5 h

Procedure:
To 5-(5-amino-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (314 mg, 1.09 mmol) suspended in water (3 mL) was added acetic acid (0.25 mL, 4.34 mmol). Once all solids had dissolved, sodium cyanate (71 mg, 1.09 mmol, dissolved in 1.5 mL water) was added dropwise. After 30 minutes, the reaction was concentrated and purified with silica gel column chromatography eluting with 92/8/0.1 dichloromethane/methanol/ammonium hydroxide to yield [5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-urea as an off-white solid (244 mg, 68%, M+H)+=333), which was converted to a hydrochloride salt:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC1(C)CC(=O)c2ccc(-c3ccc(Cl)cc3)cc21
Temperature: 25 °C

Procedure:
To a stirred solution of trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester (0.25 g, 0.81 mmol) in glyme (7 mL) was added 4-chlorophenyl boronic acid (0.19 g, 1.22 mmol), a solution of sodium carbonate (0.26 g, 2.43 mmol) in water (1.5 mL), and tetrakis(triphenylphosphine)palladium (0) (0.05 g, 0.04 mmol). The resulting solution was heated to reflux for 2 hours. The mixture was cooled to room temperature, concentrated, taken up in ethyl acetate and filtered through a pad of the Celite® reagent. The filtrate was concentrated and the residue was purified by Gilson high performance liquid chromatography (HPLC—10 to 100 acetonitrile in water) to afford 5-(4-chlorophenyl)-3,3-dimethylindan-1-one as a white solid. (0.11 g, 50%). MS (ES) m/z 271.0; HRMS: calcd for C17H15ClO+H+, 271.0884; found (ESI, [M+H]+), 271.0877.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([C:6]1[C:7]2[C:8]3[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=S)[C:9]=3[CH:16]=[CH:17][CH:18]=2)(=[O:5])=[O:4].[N:20]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][N:22]=[CH:21]1>C(O)C>[N:20]1([CH2:25][CH2:26][CH2:27][NH:28][C:10]2[C:9]3[CH:16]=[CH:17][CH:18]=[C:7]4[C:8]=3[C:12](=[CH:13][CH:14]=[C:6]4[S:3]([N:2]([CH3:19])[CH3:1])(=[O:5])=[O:4])[N:11]=2)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: CN(C)S(=O)(=O)c1ccc2c3c(cccc13)C(=S)N2
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: CN(C)S(=O)(=O)c1ccc2c3c(cccc13)C(NCCCn1ccnc1)=N2
Yield: 41.2 %

Procedure:
A mixture 5 g of 1,2-dihydro-N,N-dimethyl-2-thioxobenz[cd]indole-6-sulfonamide, 2.3 g of 3-(1H-imidazol-1-yl)propanamine, 100 ml of ethanol and 5.4 g of mercuric acetate was reacted as described in Example 1, giving 2.7 g of the desired product, mp 199°-201° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([OH:22])=[CH:17][C:16]=1[CH3:23]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([OH:22])=[CH:17][C:16]=2[CH3:23])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: Cc1cc(O)cc(C)c1-c1ccc(C(C)(C)C)cc1

Procedure:
This compound is made in a substantially similar manner as exemplified in Preparation 26 staring from 4-tert-butyl-phenyl boronic acid and 4-bromo-3,5-dimethyl phenol.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][NH:12][CH:13]=[O:14].[CH2:15]=O>C(O)=O>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:10][CH2:11][N:12]([CH:13]=[O:14])[CH2:15]2
Reactant: COc1cccc(CCNC=O)c1C
Reactant: C=O
Solvent: O=CO
Product: COc1ccc2c(c1C)CCN(C=O)C2
Temperature: 100 °C

Procedure:
To a solution of {2-[2-methyl-3-(methyloxy)phenyl]ethyl}formamide (Preparation 11; 1.93 g; 10.0 mmol) in formic acid (20 ml) was added paraformaldehyde (0.315 g; 10.5 mmol) and the resulting mixture was heated under reflux (100° C.) for 20 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([CH:9]2[C:17](=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=O)=O)=[CH:5][CH:4]=1.O.[NH2:23][NH2:24]>>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]2[C:9]3[CH2:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]=3[NH:23][N:24]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(=O)C2C(=O)c3ccccc3C2=O)cc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 0 °C

Procedure:
A mixture of 2-(4-methoxybenzoyl)indan-1,3-dione (1.4 g, prepared by a modification of the method disclosed in J. Het. Chem. 8, 855-859 (1971)), and hydrazine hydrate (15 ml) was boiled under reflux for 24 hours. The mixture was cooled, poured into ice-water and the solid which precipitated was collected by filtration, washed with absolute ethanol and dried to give 3-(4-methoxyphenyl)-1,4-dihydroindeno[1,2-c]pyrazole, m.p. 247° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 90 °C
Yield: 106.4 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (20 g, 111.10 mmol) in AcN (200 mL) were added K2CO3 (145.9 g, 333.30 mmol) and 2-(chloromethyl)quinoline (28.50 g, 133.32 mmol) at RT. The reaction mixture was heated at 90° C. for 12 h and then cooled to RT and filtered. The filtrate was concentrated in vacuo. The residue was then diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water, a saturated NH4Cl solution, and then dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (38.0 g, 89%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]=O)[CH:28]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: O=Cc1cccnc1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NCc2cccnc2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
The aniline prepared in Example 308C (180 mg, 0.48 mmol) and 3-pyridine carboxaldehyde (55 mg, 0.51 mmol) were combined in methanol (4 mL) and sodium cyanoborohydride (48 mg, 0.77 mmol) was added followed by 100 mg of crushed molecular sieves. The reaction was adjusted to pH6 with acetic acid and stirred at 25° C. for 3 hours. The reaction was concentrated and transferred directly to a column of silica gel and purified by flash chromatography (5% methanol-ethyl acetate) to give the tide compound (182 mg, 82%) as an oil that solidified after standing. 1H NMR (300 MHz, CD3OD) δ 8.54 (d, J=2.4 Hz, 1H), 8.40 (dd, J=5.1, 1.3 Hz, 1H), 7.84 (bd, J=8.4 Hz, 1H), 7.65-7.55 (m, 1H), 7.40 (dd, J=7.8, 4.7 Hz, 1H), 7.30-7.10 (m, 4H), 6.66 (dd, J=8.8, 2.3 Hz, 1H), 6.37 (d, J=2.3 Hz, 1H), 4.45 (s, 2H), 3.64 (s, 3H), 2.10-1.98 (m, 8H), 1.90-1.78 (m, 1H), 1.65-1.55 (m, 1H). MS (CI) 464 (M+H)+. HRMS FAB Calcd m/z MH+ for C26H29O3N3S 464.2008, found 464.2023.
Reaction SMILES: [CH:1]12[O:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]2.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>CC(O)C.O>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([O:21][CH2:20][C@@H:18]([OH:17])[CH2:19][N:7]2[CH2:6][CH:5]3[O:9][CH:1]([CH2:2][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]3)[CH2:8]2)=[CH:23][CH:24]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: N#Cc1ccc(OC[C@@H]2CO2)cc1
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CN(C[C@H](O)COc3ccc(C#N)cc3)CC(C1)O2
Yield: 100 %

Procedure:
A mixture of tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (prepared in an analogous fashion to the compound of Preparation A(vi) above; 0.72 g, 3.2 mmol) and 4-[(2S)-oxiranylmethoxy]benzonitrile (from step (i) above; 0.56 g, 3.2 mmol) in IPA/water (11 mL of 10:1) was stirred at 60° C. for 18 h. The solvent was then evaporated to give 1.3 g (100%) of the sub-title compound, which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]2([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:45][CH2:44]2)[N:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]4([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:45][CH2:44]4)[N:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CS(=O)(=O)C1(c2cccc(Br)n2)CC1
Product: C[C@@H](c1ccc(-c2cccc(C3(S(C)(=O)=O)CC3)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 76 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 2-bromo-6-(1-methanesulfonyl-cyclopropyl)-pyridine following a procedure analogous to that described in Example 1. Yield: 76% of theory; LC (method 1): tR=1.93 min; Mass spectrum (ESI+): m/z=549 [M+H]+.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([N:23]([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)C=CC=CC=1.[NH:27]1[CH2:31][CH2:30][CH:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:28]1>O1CCOCC1>[CH3:25][N:23]([CH3:24])[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12][CH:11]([CH2:10][NH:9][C:8]([N:27]2[CH2:31][CH2:30][CH:29]([C:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[NH:34][CH:33]=3)[CH2:28]2)=[O:26])[CH2:16][CH2:15]1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Reactant: c1ccc2c(C3CCNC3)c[nH]c2c1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)N2CCC(c3c[nH]c4ccccc34)C2)CC1
Yield: 37.3 %

Procedure:
The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (519 mg, 1.47 mmole) was added to a solution of 3-pyrrolidine-3-yl-1H-indole (274 mg, 1.47 mmole) in dioxane (12 ml). The reaction mixture was then boiled under reflux for 12 hours. The reaction mixture was worked up by distilling off the solvent. The residue contained, apart from phenol, also the two diastereoisomers of 3-(1H-indol-3-yl)pyrrolidine-1-carboxylic acid-(4-dimethyl amino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (50 g). Methanol/EE (1:1; 1000 ml) was used as eluent. The non-polar diastereoisomer of 3-(1H-indol-3-yl)pyrrolidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (234 mg, m.p. 101°-103° C., 36%) and the polar diastereoisomer of 3-(1H-indol-3-yl)pyrrolidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (244 mg, m.p. 103°-106° C., 37%) were thereby obtained in pure form.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([O:27]CC)=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:37])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([C:25]([OH:27])=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([NH:35][C:36]([CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)=[O:37])[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(NC(=O)C3CCCCC3)cc2n1Cc1ccc(OC(C(=O)OCC)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2c(C)cc(NC(=O)C3CCCCC3)cc2n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-4-methyl-1-[4-[(α-ethoxycarbonyl)benzyloxy]benzyl]-6-cyclohexylcarbonylaminobenzimidazole and 2N sodium hydroxide solution in ethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]#[N:14])[NH:10]2)=[CH:6][CH:5]=1)([O-])=O>[Ni].CCO>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]#[N:14])[NH:10]2)=[CH:6][CH:5]=1
Reactant: N#Cc1cc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Ni]
Solvent: CCO
Product: N#Cc1cc2ccc(N)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
A mixture of 6-nitro-1H-indole-2-carbonitrile (2.5 g, 13 mmol) and Raney Nickel (500 mg) in EtOH (50 mL) was stirred at room temperature under H2 (1 atm) for 1 h. Raney Nickel was removed via filtration and the filtrate was evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica get to give 6-amino-1H-indole-2-carbonitrile (1.0 g, 49%). 1H NMR (DMSO-d6) δ 12.75 (br s, 1H), 7.82 (d, J=8 Hz, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 7.15 (d, J=8 Hz, 1H); MS (ESI) m/e (M+H+) 158.2.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][NH:11][CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1.Cl[C:18]1[CH:23]=[CH:22][C:21]2=[N:24][C:25]([C:27]3[CH:28]=[CH:29][C:30]([CH3:40])=[C:31]([NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH:32]=3)=[CH:26][N:20]2[N:19]=1>C(O)CCC>[CH3:36][C:35]([CH3:38])([CH3:37])[C:34]([NH:33][C:31]1[CH:32]=[C:27]([C:25]2[N:24]=[C:21]3[N:20]([CH:26]=2)[N:19]=[C:18]([N:14]2[CH2:15][CH2:16][CH:12]([NH:11][CH3:10])[CH2:13]2)[CH:23]=[CH:22]3)[CH:28]=[CH:29][C:30]=1[CH3:40])=[O:39]
Reactant: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1NC(=O)C(C)(C)C
Reactant: CNC1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CNC1CCN(c2ccc3nc(-c4ccc(C)c(NC(=O)C(C)(C)C)c4)cn3n2)C1
Temperature: 180 °C
Yield: 14.8 %

Procedure:
An small microwave vial is charged butanol (0.183 mL), diisopropylethylamine (0.122 mL, 0.7 mmol), N-methylpyrrolidin-3-amine (0.050 g, 0.5 mmol), and N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-methyl-phenyl]-2,2-dimethyl-propanamide (0.0397 g, 0.1 mmol). The vial is sealed and heated at 180° C. for 30 min in microwave. The mixture is concentrated, taken up in DMSO and purified on reverse phase preparative HPLC with gradient (15% B:85% A to 100% B, where solvent A=95% water, 5% acetonitrile and 0.1% TFA; solvent B=90% acetonitrile, 10% water and 0.1% TFA) to give the title compound (0.006 g, 15% yield). LCMS m/z=407.6 [M+H]+, tR=1.32 min. (compound same as Example 360)
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])[NH:3][C:2]1=[O:11].[Br:12]Br>C(O)(=O)C>[Br:12][C:7]1[C:6]2[NH:1][C:2](=[O:11])[NH:3][C:4](=[O:10])[C:5]=2[S:9][CH:8]=1
Reactant: BrBr
Reactant: O=c1[nH]c(=O)c2sccc2[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2scc(Br)c2[nH]1
Temperature: 80 °C
Yield: 56.1 %

Procedure:
To 250 ml of a solution of 7.31 g (52.2 mmol) of thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione in acetic acid was added 25.0 g (156 mmol) of bromine at room temperature, followed by heating at 80° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Ice water was added to the residue, followed by filtering out crystals thus precipitated to give 7.24 g (yield: 56.2%) of the title compound.
Reaction SMILES: Br[C:2]([CH3:18])([CH3:17])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[CH3:19][O-:20].[Na+]>CO>[CH3:17][C:2]1([CH3:18])[O:4][C:3]1([O:20][CH3:19])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1
Reactant: CC(C)(Br)C(=O)c1ccc(N2CCCCC2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC1(c2ccc(N3CCCCC3)cc2)OC1(C)C

Procedure:
12.0 g (38.7 mmol) of 2-bromo-2-methyl-1-(4-piperidinophenyl)-propan-1-one are dissolved in 20 ml of methanol, and 7.0 g (46.4 mmol) of methanolic 30% strength sodium methylate solution are then added dropwise at room temperature. The methanol is then distilled off under reduced pressure. The residue is taken up in toluene, and the precipitated salt is filtered off. The solution is concentrated in vacuo. The brown residue, which is a slowly crystallising liquid, is directly further reacted.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[O:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]([F:13])([F:14])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12])=[O:4]
Reactant: O=C(NCCCCCCO)C(F)(F)F
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=CCCCCCNC(=O)C(F)(F)F
Temperature: 23 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To 2.1 gm (10.1 mmole) of the 6-trifluroacetamido-1-hexanol in 40 ml of methylene chloride was added 3 gm (10.64 mmole) of pyridinium dichromate and 4.4 gm of 3 Angstrom molecular sieves, and the reaction was allowed to proceed with stirring for 3 hours at 23° C. After addition of 250 ml of ethyl acetate, the reaction mixture was filtered through a small bed of silica gel 60 and concentrated in vacuo. Flash chromatography using 50% (v/v) ethyl acetate in hexane afforded 1.48 gms (70%) of 6-trifluroacetamido-1-hexanal. ##STR16##
Reaction SMILES: [C:1]1([P:7](Cl)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH2:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:18][CH2:17]1>C1COCC1>[C:1]1([P:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH2:28][CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[CH2:18][CH2:17]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CCc1cccnc1)NCCCCC1CCN(P(=O)(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
3.4 ml (17.3 mmol) diphenylphosphinic acid chloride are dissolved in 100 ml absolute THF and cooled to ca. 0° C. under moisture exclusion. 5.0 g (17.3 mmol) N-(4-piperidin-4-yl-butyl)-3-(pyridin-3-yl)-propionamide and 4.8 ml (34.6 mmol) TEA are dissolved in 50 ml absolute THF and added dropwise under ice cooling. The mixture is stirred for three days at RT without further cooling. Subsequently, the solvent is removed under vacuum to a large extent and the residue is taken up in 100 ml 10% sodium hydroxide solution and extracted twice, each with 150 ml CHCl3. The combined organic phases are washed with saturated NaCl-solution, dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (90/10) and crystallized from diisopropyl ether after drawing off the solvent. Colorless crystals with an MP of 134-135° C. yield 5.3 g (62%).
Reaction SMILES: I[CH2:2][CH3:3].Cl.[NH:5]1[CH2:9][CH2:8][C@@H:7]([CH2:10][C:11]#[N:12])[CH2:6]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:2]([N:5]1[CH2:9][CH2:8][C@@H:7]([CH2:10][C:11]#[N:12])[CH2:6]1)[CH3:3]
Reactant: N#CC[C@@H]1CCNC1
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CC[C@@H](CC#N)C1
Yield: 51 %

Procedure:
Iodoethane (10.1 g) was added to a mixture of 2-((S)-pyrrolidin-3-yl)acetonitrile hydrochloride (Intermediate 205, 7.9 g) and potassium carbonate (29.7 g) in DMF (20 mL) and the resultant mixture was stirred at room temperature for 5 hours. Water was added and the mixture was extracted with ethyl acetate, washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 2-((S)-1-ethylpyrrolidin-3-yl)acetonitrile (3.8 g) as a yellow oil which was used without further characterisation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11]C)[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COc1cc(Br)cc(C=O)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(Br)cc(O)c1O
Temperature: 25 °C
Yield: 90 %

Procedure:
To dichloromethane (400 mL) was added 5-bromo-2-hydroxy-3-methoxy-benzaldehyde (prepared per Synthetic Communications, 1991 ;21 (8,9):1091-5; 94.6 g, 409.4 mmol). To this was added with cooling to 10° C. a solution of boron tribromide (153.9 g, 614 mmol) in dichloromethane (400 mL) over 20 minutes, followed by warming to 25° C. overnight. The mixture was poured into 2 L of ice and extracted with chloroform. The chloroform solution was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo and hexane was added giving a crystalline precipitate which was filtered, washed with hexane, and dried in vacuo to a solid, 80.0 g, 90% yield. NMR spectraand elemental analysis were consistent with the structure.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14]C(=O)OCC3C=CC=CC=3)=[C:10]([O:25][CH:26]([CH3:28])[CH3:27])[CH:9]=2)[CH2:6][CH2:5][N:4]([CH3:29])[CH2:3]1>CO>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([CH3:29])[CH2:3][CH:2]2[OH:1])=[CH:9][C:10]=1[O:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)Oc1cc(C2CCN(C)CC2O)ccc1NC(=O)OCc1ccccc1
Solvent: CO
Product: CC(C)Oc1cc(C2CCN(C)CC2O)ccc1N
Yield: 94 %

Procedure:
178 mg of benzyl [4-(3-hydroxy-1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate (mixture of the cis diastereoisomers) are dissolved in 45 ml of methanol. The solution is filtered on 0.45 μm Acrodisc and then hydrogenated in an H-cube (Pd/C 10% cartridge and P H2=1 atm). The reaction medium is evaporated to dryness under reduced pressure, so as to give 111 mg of 4-[4-amino-3-(propan-2-yloxy)phenyl]-1-methylpiperidin-3-ol in the form of an orangey-coloured solid (mixture of the cis diastereoisomers).