Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:41])[N:12]([CH2:15][C:16]3[N:17]=[CH:18][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12>C(O)(=O)C.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:41])[N:12]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)N(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]cnc1CN1CCc2c(C)c3ccccc3n2C1=O
Temperature: 65 °C
Yield: 90.6 %

Procedure:
A solution of 3,4-dihydro-5-methyl-2-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrimido[1,6-a]indol-1(2H)-one (0.9 g) in a mixture of acetic acid and water (4:1, 30 ml) was heated at 65° C. for 3.5 hours. After evaporation of the solvent, the residue was neutralized with aqueous sodium bicarbonate solution and extracted three times with chloroform. The chloroform layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (5% methanol-chloroform) to give 3,4-dihydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]pyrimido[1,6-a]indol-1(2H)-one (0.447 g) as a powder. This powder was dissolved in a mixture of methanol (40 ml) and 12N hydrochloric acid (0.3 ml). The solution was evaporated to 4 ml and then diluted with ether. The solution was allowed to stand at room temperature to give 3,4-dihydro-5-methyl-2-[(5-methyl- 1H-imidazol-4-yl)methyl]pyrimido[1,6-a]indol-1(2H)-one hydrochloride (387 mg).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)=[CH:11][CH:10]=1.OCCI>CN(C)C=O>[OH:4][CH2:2][CH2:1][N:16]1[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[N:19]=[C:15]1[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:14][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1
Agent: OCCI
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(C(F)(F)F)cn2CCO)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
At an internal temperature of 0°-50°, 35.0 g of potassium tert.-butoxide are added to a solution of 35 g of 2-(4-methoxyphenyl)-4-(trifluoromethyl)-imidazole in 200 ml of dimethylformamide. After 20 minutes, a solution of 14.7 ml of 2-hydroxyethyl iodide in 100 ml of dimethylformamide is added dropwise within a period of 5 minutes, the mixture is then stirred for 120 hours at room temperature and the solvent is removed in a rotary evaporator; the residue is taken up in water and extracted several times with ethyl acetate. The organic phases are combined, the solvent is removed and the residue is chromatographed on silica gel with the solvent mixture ethyl acetate/hexane 1:1 and 1-(2-hydroxyethyl)-2-(4-methoxyphenyl)-4-(trifluoromethyl)-1H-imidazole is isolated from the main fractions in the form of a crystallising oil.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[N:8]([CH3:12])[C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>CO.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]2[N:8]([CH3:12])[C:9](=[O:11])[S:10][C:6]=2[CH:5]=1
Reactant: Cn1c(=O)sc2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(=O)sc2cc(N)ccc21

Procedure:
A mixture of 6-nitro-3-methyl-2-benzothiazolinone (J. Heterocyclic Chem. 1992, 29, 1069-1076, 4.85 g, 23.1 mmol) and 10% palladium-on-carbon (491 mg, 0.461 mmol) in a mixture of MeOH (45 mL) and tetrahydrofuran (45 mL) is shaken under a 40 psi hydrogen atmosphere on a Parr apparatus for 17 h. The catalyst is removed by filtration through a pad of Celite, and the filtrate is concentrated under reduced pressure and triturated with ethyl acetate/hexanes. Filtration then provides the title compound, mp 188-190° C.; MS (ESI+) for C8H8N2OS m/z 181 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][CH2:35][O:36][C:37]1[CH:43]=[C:42]([CH:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][CH3:52])[CH2:46][CH2:45]2)[CH:41]=[CH:40][C:38]=1[NH2:39].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:38]3[CH:40]=[CH:41][C:42]([CH:44]4[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][CH3:52])[CH2:48][CH2:49]4)=[CH:43][C:37]=3[O:36][CH2:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: CCCN1CCC(c2ccc(N)c(OCC)c2)CC1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCCN1CCC(c2ccc(Nc3nccc(-c4c(-c5cccc(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OCC)c2)CC1
Temperature: 130 °C
Yield: 58.9 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 2-(2-ethyloxy)-4-(1-propyl-4-piperidinyl)aniline (Example 154, step E) (51 mg, 0.19 mmol), and p-toluenesulfonic acid (98 mg, 0.51 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (32 mg, 0.112 mmol, 24%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.36 (d, J=6.78 Hz, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 8.27 (d, J=5.31 Hz, 1H), 8.04 (d, J=7.87 Hz, 1H), 7.80 (d, J=7.87 Hz, 1H), 7.73 (d, J=8.97 Hz, 1H), 7.65 (d, J=8.06 Hz, 1H), 7.59 (t, J=7.78 Hz, 1H), 7.42-7.49 (m, 1H), 7.34-7.42 (m, 1H), 7.19 (t, J=8.06 Hz, 2H), 6.98 (t, J=6.78 Hz, 1H), 6.93 (s, 1H), 6.76 (d, J=8.42 Hz, 1H), 6.55 (d, J=5.13 Hz, 1H), 4.08 (q, J=6.90 Hz, 2H), 2.88-3.00 (m, 2H), 2.38-2.45 (m, 1H), 2.19-2.30 (m, 2H), 1.87-1.99 (m, 2H), 1.63-1.75 (m, 4H), 1.39-1.49 (m, 2H), 1.26 (t, J=6.96 Hz, 3H), 0.84 (t, J=7.23 Hz, 3H). MS (ESI): 688 [M+H]+.
Reaction SMILES: [I:1]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[C:27]([O:35][C@H:36]1[C:40]([F:42])([F:41])[CH:39](O)[O:38][C@@H:37]1[CH2:44][O:45][C:46]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl.CCCCCC>[C:27]([O:35][C@H:36]1[C:40]([F:42])([F:41])[CH:39]([I:1])[O:38][C@@H:37]1[CH2:44][O:45][C:46]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O[C@@H]1[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(O)C1(F)F)c1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(O[C@@H]1[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(I)C1(F)F)c1ccccc1
Reaction time: 0.5 h
Yield: 113.4 %

Procedure:
I2 (0.524 g) and dichloromethane (8 mL) were charged into a round bottom flask in the dark. To this solution was added dropwise a solution of Ph3P (0.634 g) in dichloromethane (8 mL) at ambient temperature. The resulting suspension was stirred at this temperature for 30 minutes and imidazole (0.734 g) was added. After the resulting suspension was stirred for 5 minutes at room temperature, a solution of lactol 8 (0.8 g) in dichloromethane (8 mL) was added dropwise and the resulting solution was stirred overnight at room temperature. Hexane (30 mL) was added and then the suspension was stirred for 10 minutes, filtered, and concentrated to give 1.1 g of (2R,3R)-4,4-difluoro-5-iodo-2-(trityloxymethyl)tetrahydrofuran-3-yl benzoate 10.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][O:48][CH2:49][C:50](Cl)=[O:51].C(N(CC)CC)C>O1CCCC1>[CH3:47][O:48][CH2:49][C:50]([NH:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:20]=[CH:19][N:18]([C:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:17]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:51]
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5[-1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.125 g, 0.207 mmol), in tetrahydrofuran (5 mL), were added, 2-methoxy acetyl chloride (0.034 g, 0.315 mmol, 0.025 mL) and triethylamine (0.107 g, 1.06 mmol, 0.147 mL). The reaction mixture was stirred at room temperature for 12 hours. After evaporation of the solvent, the residue was dissolved in 10 mL of ethyl acetate and was washed 3 times with water (5 mL). The crude was used without further purification (0.141 g, 99% yield): ES-MS (m/z) 675 [M+1]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]=[C:15]([C:17]([OH:19])=O)[O:14][N:13]=2)=[CH:8][CH:7]=1>CN(C)C=O>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]=[C:15]([C:17]([Cl:3])=[O:19])[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)on2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)Cl)on2)cc1

Procedure:
Using 40 ml of thionyl chloride, 7.3 g (35.9 mmol) of 3-(4 -methylphenyl) isoxazole-5-carboxylic acid obtained above in the procedure (2) were refluxed for 4 hours in the presence of 0.1 ml of dimethylformamide. Thionyl chloride was distilled off under reduced pressure, followed by the addition of 100 ml of benzene. The resultant mixture was distilled under reduced pressure so that 3-(4-methylphenyl) isoxazole-5-carboxylic acid chloride was obtained as a solid. The solid was provided for the next step without purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[N:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1>>[CH3:22][C:19]1[N:18]=[N:17][C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])=[CH:21][CH:20]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Cc1ccc(I)nn1
Product: Cc1ccc(C#Cc2c(-c3ccccc3)noc2C)nn1
Yield: 80 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (70 mg, 0.38 mmol) was converted (using 3-iodo-6-methyl-pyridazine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 84 mg, 80%) which was obtained as a light brown solid. MS: m/e=276.1 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]([CH2:33][O:34][C:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:12][NH:13][C:14](=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>ClCCl.N1C=CC=CC=1>[C:1]([O:10][CH:11]([CH2:33][O:34][C:35]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:12][NH:13][C:14](=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
Benzoyl chloride (30 mmol) is added dropwise at 0° C. to a solution of 10 (27.3 mmol) in 80 ml of dichloromethane/pyridine (1:1). Slow warming to room temperature is allowed to take place, and stirring is continued for another 4 hours at room temperature. The mixture is then concentrated, added twice with 50 ml of toluene and concentrated. The residue is added with 100 ml of H2O and extracted three times with 100 ml of dichloromethane. The combined organic phases are washed with 50 ml of cold 5% HCl and 50 ml of saturated NaCl solution, dried over MgSO4, filtrated and concentrated. The residue is purified by silica gel chromatography using heptane/ethyl acetate (3:1). Yield: 87% of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:23])[O:4][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:25]([O:16][C:13]1[CH:14]=[C:15]2[C:5]3([O:4][N:3]([CH3:23])[C:2]([NH2:1])=[N:6]3)[CH2:7][CH:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:9][C:10]2=[CH:11][CH:12]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1OC2(CC(c3ccccc3)Oc3ccc(O)cc32)N=C1N
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN1OC2(CC(c3ccccc3)Oc3ccc(OCc4ccccc4)cc32)N=C1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 2.5 %

Procedure:
A mixture of 3′ amino-2′-methyl-2-phenyl-2′H-spiro(chroman-4,5′-(1,2,4)oxadiazol)-6-ol (30 mg, 0.096 mmol), (bromomethyl)benzene (21.45 mg, 0.125 mmol) and K2CO3 (16 mg, 0.115 mmol) was dissolved in acetone, then the mixture was stirred at room temperature for 24 hours. The mixture was filtrated and concentrated. The residue was purified by preparative HPLC to give 6-(benzyloxy)-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]3′-amine (140) (0.95 mg, 3%). 1H-NMR (MeOD): 7.32-7.56 (m, 10H), 6.91-7.23 (m, 3H), 5.12 (d, 2H), 5.23 (t, 2H), 3.31 (s, 3H) 2.73 (m, 1H), 2.32 (m, 1H);
Reaction SMILES: C(OC([NH:11][C:12]1[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:13]=1)=O)C1C=CC=CC=1.C(O)(=O)C.[H][H]>C(O)C.[Pd]>[C:18]([OH:20])(=[O:19])[CH3:17].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)COc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)COc1ccc(N)cc1
Yield: 126.1 %

Procedure:
To a solution of the product of step (b) (5 g) in ethanol (300 ml) containing glacial acetic acid (0.8 ml) under argon was added 10% Pd on C (250 mg). The argon was replaced by hydrogen and the reaction mixture was stirred under a blanket of hydrogen for 4 hours. The catalyst was filtered off through a pad of diatomaceous earth and washed with ethanol, and the combined filtrate and washings were evaporated to dryness to yield t-butyl 4-aminophenoxyacetate, acetate salt (2.5 g) as brown oil: NMR Spectrum (DMSO-d6) 1.41 (9H, s), 1.86 (3H, s), 4.43 (2H, s), 5.12 (2H, s), 6.49 (2H, d), 6.60 (2H, m).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH3:15][O-:16].[Na+].[OH-].[Na+]>CO.O>[CH3:15][O:16][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1nc(SC)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.8 %

Procedure:
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (24.40 g, 104.9 mmol) in MeOH (125 mL) was added solid sodium methoxide (11.40 g, 211.0 mmol) at rt. The reaction mixture was stirred at rt for 5 h and then treated with NaOH (17.70 g, 315.5 mmol) in H2O (100 mL). It was then stirred at the same temperature for an additional 1 h. The reaction mixture was concentrated to half of the volume and then acidified to pH=4 with HCl (6N). The reaction was extracted with EtOAc (5×200 mL) and the organic layer was washed with brine (200 mL), dried over Na2SO4, and concentrated to yield the desired product as a white solid (19.28 g, 92%). MS (m/z): 201 (MH+). 1H NMR (DMSO-d6) δ: 8.72 (s, 1H), 3.98 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:8])[CH:5]=[CH:6][CH:7]=1.[C:9](=[O:11])=[O:10]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([OH:11])=[O:10]
Reactant: O=C=O
Reactant: Clc1cccc(Br)c1
Solvent: C1CCOC1
Product: O=C(O)c1c(Cl)cccc1Br
Temperature: -78 °C
Reaction time: 2 h

Procedure:
The mixture of 500 mg of 3-bromochlorobenzen and 3 ml of tetrahydrofuran was cooled down to −78° C. and 1.3 ml of 2.0M lithiumdiisopropylamide heptane/tetrahydrofuran/ethylbenzene was added. After stirring it for 2 hours, the mixture was put into dry ice and washed and extracted as described in Referencial Example 1 to obtain a crude material. The crude material was washed with a mixed solvent of hexane-ethyl acetate to obtain the said compound.
Reaction SMILES: [C:1]([OH:10])(=O)[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].S(Cl)([Cl:13])=O>C1C=CC=CC=1>[C:1]([Cl:13])(=[O:10])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(CCC)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCC(CCC)C(=O)Cl
Temperature: 50 °C

Procedure:
To 4.32 g (30 mmol) of valproic acid in an ice bath, thionyl chloride (3.60 g, 30 mmol) was slowly added, with stirring. The neat mixture was allowed to come to room temperature and then heated in a water bath at 50° C. for 30 minutes. 50 ml portions of dry benzene were twice added and removed under reduced pressure. The resultant product was used in subsequent reactions without further purification.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:13][CH:12]=[CH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O>>[CH2:1]([O:8][CH:9]1[CH2:10][CH:11]=[CH:12][CH:13]1[Br:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C1=CCC(OCc2ccccc2)C1
Product: BrC1C=CCC1OCc1ccccc1

Procedure:
4-Benzyloxy-1-cyclopentene is brominated with N-bromosuccinimide in the 3-position. The 4-benzyloxy-3-bromo-1-cyclopentene obtained is reacted with 1-heptanol in the presence of silver oxide and the so obtained 4-benzyloxy-3-heptyloxy-1-cyclopentene is epoxidized with m-chloro-perbenzoic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[C:25]=2[F:26])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1cccc(F)c1F
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2F)cc1[N+](=O)[O-]
Yield: 91.9 %

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) (3.64 g, 10 mmol) and 2,3-difluorobenzene boronic acid (2.35 g, 14.9 mmol) according to the general procedure B. Obtained as a yellow solid (3.22 g).
Reaction SMILES: [F:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([NH2:16])=[CH:11][CH:12]=3)[C@@:7]3([CH2:21][CH2:20][O:19][C:18]([NH2:22])=[N:17]3)[C:6]=2[CH:5]=[C:4]([O:23][CH3:24])[CH:3]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(OCC)(=O)C>[NH2:22][C:18]1[O:19][CH2:20][CH2:21][C@@:7]2([N:17]=1)[C:6]1[CH:5]=[C:4]([O:23][CH3:24])[CH:3]=[C:2]([F:1])[C:15]=1[O:14][C:13]1[C:8]2=[CH:9][C:10]([NH:16][C:32](=[O:33])[C:29]2[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][N:30]=2)=[CH:11][CH:12]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(N)ccc1O2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1O2
Reaction time: 0.03 h
Yield: 46.8 %

Procedure:
To a suspension of (S)-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthene]-2,7′-diamine (102 mg, 0.310 mmol) and 5-chloropicolinic acid (54 mg, 0.341 mmol) in ethyl acetate (2 mL) was added triethylamine (0.13 mL, 0.929 mmol) and the mixture was stirred for 2 min, followed by addition of 1-propanephosphonic acid cyclic anhydride (T3P) (50 wt. % solution in ethyl acetate) (0.37 mL, 0.619 mmol). After 2 hr at RT, the mixture was quenched with sat NaHCO3 and diluted with 3 ml EtOAc. The organic layer was separated, concentrated in vacuo, and the residue purified by FC on 12 g RediSep Gold column using 10-80% DCM/MeOH/NH4OH (90:10:1) in DCM to afford (S)—N-(2-amino-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthen]-7′-yl)-5-chloropicolinamide (68 mg, 0.145 mmol, 47% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH2:22])[C:16]=2[CH:15]=[N:14][CH:13]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:22][S:24]([CH3:23])(=[O:26])=[O:25])[C:16]=2[CH:15]=[N:14][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@@H]1CCCc2c(-c3ccc(C(F)(F)F)cc3F)cncc21
Product: CS(=O)(=O)N[C@@H]1CCCc2c(-c3ccc(C(F)(F)F)cc3F)cncc21
Yield: 60 %

Procedure:
In analogy to the procedure described for the preparation of example 2, (+)-(R)-4-(2-fluoro-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroisoquinolin-8-amine (example 74) and methanesulfonyl chloride gave the title compound as white solid in 60% yield. MS: 389.1 (M+H+).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:13].[NH:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]1>>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]([CH3:13])=[C:2]([N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:18][CH2:19]2)[CH:7]=1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: COc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)c(C)cc1[N+](=O)[O-]

Procedure:
Starting Materials: 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (INTERMEDIATE 7) and tert-butyl piperidin-4-ylcarbamate.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[C:13]([O:25][CH3:26])[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]=2[O:19][CH3:20])[CH2:11]1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:26][O:25][C:13]1[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]([O:19][CH3:20])=[C:17]2[C:12]=1[CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:36]1[CH2:37][CH2:38][N:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)[CH2:34][CH2:35]1)[CH2:18]2
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCI)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCN1CCN(c3ccccn3)CC1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
The mixture of 2-(8-iodooctyl)-4,5,6,7-tetramethoxyindan (1.20 g), 1-(2-pyridyl)piperazine (823 mg), and potassium carbonate (1.04 g) in DMF (12 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate=10:1) to yield the entitled compound (1.16 g) as an oil.