Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[CH:6]=[CH:7][CH:8]=1.[C:17](=O)([O-])[O:18]CC.C[O-].[Na+]>CO>[OH:13][CH2:12][CH:11]1[O:14][C:17](=[O:18])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:4]=2)[CH2:10]1
Reactant: OCC(O)CNc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1OC(CO)CN1c1cccc(C(F)(F)F)c1
Temperature: 110 °C

Procedure:
59 G. OF 1-(M-TRIFLUOROMETHYL PHENYLAMINO)-2,3-PROPANEDIOL AND 118 G. OF ETHYL CARBONATE ARE INTRODUCED INTO A DISTILLATION APPARATUS. The mixture is progressively heated to about 110° C. when dissolution is obtained. Then, 12 ml. of a 5% solution of sodium methylate in methanol is added thereto. The distillation of the ethanol formed during the course of the reaction is then observed. Upon completion thereof any excess ethyl carbonate is removed under reduced pressure and the residue obtained is crystallized in isopropyl ether.
Reaction SMILES: [Li+].[OH-].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[NH:13][C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]([C:27]([O:29]C)=[O:28])[CH2:15]2)=[CH:7][CH:6]=1)#[N:4].Cl>C1COCC1.CO.O>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C@@H:14]([NH:13][C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[CH:6][CH:7]=2)=[O:31])[CH2:15][C@@H:16]1[C:27]([OH:29])=[O:28])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)Nc2ccc(C#N)cc2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C#N)cc2)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
LiOH (143 mg, 5.96 mmol) was added to a solution of (2R,4R)-1-tert-butyl 2-methyl 4-(3-(4-cyanophenyl)ureido)piperidine-1,2-dicarboxylate (1200 mg, 2.98 mmol) in THF/MeOH/water (3:2:1) (24 mL) and the resulting solution was stirred at room temperature for 18 hours. 1M HCl solution was added to reaction solution to adjust pH to about 3, extracted with ethyl acetate (2×50 mL). The organic layers were dried over MgSO4 and concentrated to give the acid as a white solid 1150 mg (99%). LC-MS: 389.2, 387.3 (t=2.1 min).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2([C:10]3([CH3:15])[CH2:12][C:11]3([F:14])[F:13])[CH2:9][O:8]2)=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]([C:10]2([CH3:15])[CH2:12][C:11]2([F:14])[F:13])([OH:8])[CH2:9][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: CC1(C2(Cc3ccc(F)cc3)CO2)CC1(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C(O)(Cc2ccc(F)cc2)Cn2cncn2)CC1(F)F
Temperature: 80 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A solution of 6.3 g (0.026 mol) of 2-(4-fluorobenzyl)-2-(2,2-difluoro-1-methyl-cyclopropyl)-oxirane in 5 ml of dimethylformamide is added dropwise with stirring at 80° C. to a mixture of 4.6 g (0.066 mol) of 1,2,4-triazole and 0.5 g (0.0045 mol) of potassium tert.-butylate in 10 ml of dimethylformamide. When the addition is complete, the reaction mixture is stirred for 8 hours at 80° C. The solvent is subsequently stripped off under reduced pressure and the residue which remains is dissolved in ethyl acetate. The organic solution is washed with water, dried over sodium sulphate and concentrated under reduced pressure. The residue is chromatographed on silica gel using dichloromethane as the eluent. After the eluate has been evaporated, 1.7 g (21% of theory) of 1-(4-fluorophenyl)-2-(2,2-difluoro-1-methyl-cyclopropyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol are obtained in the form of a solid substance of melting point 114° C.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:24]=[C:23]([C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:8]=2[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[N:16][CH:17]=2)=[O:10])=[C:4](OC)[CH:3]=1.FC1C=CC(O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:24]=[C:23]([C:25]([F:31])([F:30])[C:26]([F:27])([F:29])[F:28])[CH:22]=[CH:21][C:8]=2[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[N:16][CH:17]=2)=[O:10])=[CH:32][CH:33]=1
Reactant: COc1cc(F)ccc1Oc1cc(C(F)(F)C(F)(F)F)ccc1C(=O)Nc1ccc(C(=O)O)nc1
Agent: Oc1ccc(F)cc1
Product: O=C(O)c1ccc(NC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2Oc2ccc(F)cc2)cn1

Procedure:
5-(2-(4-Fluorophenoxy)-4-(perfluoroethyl)benzamido)picolinic acid (73) was prepared as described above for compound 72 from 4-fluorophenol.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[CH2:11][CH2:12][N:13]([CH3:51])[C@@H:14]1[CH2:21][N:20]2[C:22]3[CH:23]=[C:24]([C:35]([NH:37][S:38]([N:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)(=[O:40])=[O:39])=[O:36])[CH:25]=[CH:26][C:27]=3[C:28]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:19]2[C:18]2[CH:47]=[CH:48][CH:49]=[CH:50][C:17]=2[O:16][CH2:15]1>CC#N>[CH:29]1([C:28]2[C:27]3[CH:26]=[CH:25][C:24]4=[CH:23][C:22]=3[N:20]3[CH2:21][C@H:14]([CH2:15][O:16][C:17]5[C:18]([C:19]=23)=[CH:47][CH:48]=[CH:49][CH:50]=5)[N:13]([CH3:51])[CH2:12][CH2:11][N:44]2[CH2:43][CH2:42][N:41]([CH2:46][CH2:45]2)[S:38](=[O:40])(=[O:39])[NH:37][C:35]4=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CN(CCCl)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N4CCNCC4)cc3n2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1CCN2CCN(CC2)S(=O)(=O)NC(=O)c2ccc3c(C4CCCCC4)c4n(c3c2)C[C@@H]1COc1ccccc1-4
Yield: 26 %

Procedure:
DIPEA (20 eq) was added to a solution of (7R)-7-[(2-chloroethyl)(methyl)amino]-14-cyclohexyl-N-(piperazin-1-ylsulfonyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxamide (0.001 M) in MeCN and the mixture irradiated in a microwave (SmithCreator) at 150° C. for 5 mins. The volatiles were removed in vacuo and the residue purified by RP-HPLC, eluting with MeCN/TFA buffered with 0.1% TFA gradient. Fractions containing the product were combined and freeze dried to afford the product as a white powder (26% overall for steps 2 through to 6). 1H NMR (600 MHz, DMSO-d6+TFA, 330 K) δ 1.12-1.20 (m, 1H), 1.29-1.37 (m, 2H), 1.47-1.49 (m, 1H), 1.68-1.72 (m, 2H), 1.82-1.99 (m, 4H), 2.43 (s, 3H), 2.69-2.74 (m, 1H), 2.96-2.99 (m, 1H), 3.12-3.19 (m, 1H), 3.31-3.61 (m, 8H), 3.71-3.89 (m, 2H), 4.03-4.07 (m, 1H), 4.11-4.18 (m, 2H), 4.52-4.58 (m, 1H), 4.62-4.68 (m, 1H), 7.32-7.35 (m, 2H), 7.40-7.42 (m, 1H), 7.48 (d, J 8.4, 1H), 7.55-7.58 (m, 1H), 7.91 (d, J 8.4, 1H), 7.95 (s, 1H); (ES+) m/z 592 (M+H)+.
Reaction SMILES: [C:1]1([OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17]>CN(C=O)C>[C:16](=[O:17])([O:12][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][C:16](=[O:17])[O:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:4]=[CH:3][CH:2]=1)[O:18][CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: Oc1cccc2cccc(O)c12
Reactant: CC(C)COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)COC(=O)Oc1cccc2cccc(OC(=O)OCC(C)C)c12
Temperature: 25 °C
Yield: 31.1 %

Procedure:
To a round-bottom flask is charged naphthalene-1,8-diol (4.0 g, 25 mmol), and anhydrous DMF (50 ml). The flask is immersed in an ice-water bath, and 60% sodium hydride in mineral oil (2.4 g, 60 mmol) is added in portions. The mixture is stirred for an hour. Isobutyl chloroformate (8.2 g, 60 mmol) is added dropwise. After gradually warming to room temperature, the mixture is stirred overnight. The mixture is poured into ice-cold water and extracted with ether three times. The combined ether extracts are washed with water, then brine, and then dried over magnesium sulfate. After filtration, the filtrate is concentrated, and the residue is purified by flash column chromatography on silica gel to yield 2.8 g (31%) of the product as a light-grey solid. 1H NMR (400 MHz, CDCl3, ppm) δ 7.79 (dd, 2H, J=1.2, 8.0 Hz), 7.47 (dd, 2H, J=7.6, 8.0 Hz), 7.26 (dd, 2H, J=1.2, 7.6 Hz), 4.07 (d, 4H, J=6.8 Hz), 2.07 (m, 2H), 1.00 (d, 12 H, J=6.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([CH2:15][CH3:16])[C:9]#[C:10][C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.O.[Li+].[OH-]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:36])[CH3:37])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([CH2:15][CH3:16])[C:9]#[C:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CCC(C#CC(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C#CC(=O)O)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound from step A (100 mg, 0.17 mmol, enantiomer A) in MeOH (5 mL) was added H2O (1 mL), LiOH (72 mg, 1.7 mmol). The mixture was stirred at RT overnight. After removing the organic solvent, the residue was dissolved with H2O (5 mL) and adjusted to pH=4 with 1M HCl, then extracted with ethyl acetate, and washed with brine (20 mL), dried over dry sodium sulfate, then filtered. The solvent was evaporated to give the title compound. LC/MS m/z=583.0 [M+Na]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[OH:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([O:42][CH3:43])[CH:34]=1)=[O:32])[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[C:13]([O:12][C:11]([N:10]([CH2:18][C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[OH:20])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:36]2[CH:37]=[CH:38][C:33]([C:31]([O:30][CH2:28][CH3:29])=[O:32])=[CH:34][C:35]=2[O:42][CH3:43])=[CH:3][CH:4]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](O)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc(B(O)O)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)c(OC)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
To a solution of tert-butyl [2-(4-bromophenyl)ethyl]-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (365 mg) in 1,2-dimethoxyethane (6 ml) was added [4-(ethoxycarbonyl)-2-methoxyphenyl]boronic acid (216 mg), tetrakis(triphenylphosphine)palladium (46 mg) and aqueous solution of sodium carbonate (2M, 0.85 ml), and the mixture was stirred at 80° C. for 4 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give ethyl 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-amino]ethyl]-2-methoxy-1,1′-biphenyl-4-carboxylate (222 mg).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[C@H:16]2[C@H:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][N:17]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H][H]>CO.C1COCC1.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH:1]2[CH2:2][CH2:3]2)(=[O:6])=[O:5])=[C:8]([C@H:16]2[C@H:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][N:17]2[C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH:9]=1
Reactant: [H][H]
Reactant: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc([N+](=O)[O-])ccc1S(=O)(=O)C1CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc(N)ccc1S(=O)(=O)C1CC1
Yield: 102.8 %

Procedure:
To 76F (1.6 g) in methanol (40 mL) and THF (20 mL) was added 10% Pd/C (500 mg). The mixture was hydrogenated with a hydrogen balloon for 2.0 h. The Pd/C was removed by filtration and the filtrate was concentrated to afford 76H (1.54 g, 95% yield). 1H NMR (400 MHz, DMSO-d6, 100° C.) δ ppm 0.86-0.97 (m, 2H) 0.98-1.06 (m, 3H) 1.13-1.24 (m, 4H) 1.30 (s, 9H) 1.98 (dd, J=12.09, 8.24 Hz, 1H) 2.16 (d, J=11.54 Hz, 1H) 2.68 (s, 1H) 2.83 (d, J=7.15 Hz, 1H) 3.42 (d, J=7.15 Hz, 1H) 3.61-3.71 (m, 1H) 4.11 (q, J=7.15 Hz, 2H) 5.74 (s, 1H) 6.50-6.57 (m, 2H) 7.47 (d, J=9.34 Hz, 1H), LC-MS 439 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1>[CH2:28]([NH:35][CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:16]([C:8]2[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([F:1])=[CH:3][CH:4]=3)[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:17])[CH2:19][CH2:20]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: O=CC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(c1cc2ccccc2n1Cc1ccc(F)cc1)N1CCC(CNCc2ccccc2)CC1
Reaction time: 14 h

Procedure:
1-(1-(4-fluorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carbaldehyde (52 mg, 0.143 mmol) was dissolved in THF (2 mL) and benzylamine (0.025 mL, 0.285 mmol) was added. The solution was stirred at rt for 10 h, at which time the THF was removed in vacuo and the residue dissolved in EtOH (5 mL), and sodium cyanoborohydride (18 mg, 0.285 mmol) and a catalytic drop of glacial acetic acid were added. Stirring was permitted for 14 h, at which time the solvent was removed in vacuo, the residue was taken up in EtOAc. The organic phase was washed with 10% aq. sodium carbonate, dried over magnesium sulfate, and concentrated. Purification was accomplished via silica gel flash chromatography (30 g silica gel, 5:95 7M methanolic ammonia:ethyl acetate.) The title compound was obtained as a yellow oil. (Yield: 23 mg, 0.050 mmol, 40%) 1H NMR (400 MHz, CDCl3) 7.63, 7.37-7.23, 7.14, 7.12-7.02, 6.89, 6.59, 5.46, 4.62, 4.09, 3.76, 2.75, 2.44, 1.98-0.49
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>>[N:1]1([C:7]2[N:8]=[C:9]3[N:17]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[C@H:16]([C:18]([F:20])([F:21])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Ic1cccnc1
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2c1cccnc1

Procedure:
The product is prepared according to the procedure described in Example 12, using 200 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) and 380 mg of 3-iodopyridine. After purification by silica chromatography (elution gradient of CH2Cl2 to CH2Cl2/MeOH 96/04), 48 mg of (S)-2-morpholin-4-yl-9-pyridin-3-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:14])[C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.O=S(Cl)Cl.[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23]>>[OH:24][CH:21]([CH2:22][OH:23])[CH2:20][NH:19][C:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH3:14])[C:2]=1[Cl:1])=[O:13]
Reactant: Cn1c(Cl)c(C(=O)O)c2ccccc21
Reactant: NCC(O)CO
Solvent: O=S(Cl)Cl
Product: Cn1c(Cl)c(C(=O)NCC(O)CO)c2ccccc21
Yield: 46 %

Procedure:
Similar reaction of 2-chloro-1-methylindole-3-carboxylic acid [XXI] with SOCl2 and 3-aminopropane-1,2-diol gave N-(2,3-dihydroxypropyl)-2-chloro-1-methylindole-3-carboxamide [XXII: R6 =H;, R7 =CH2CH(OH)CH2OH] (46%) as an oil.
Reaction SMILES: C([O:8][C:9]1[C:14]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:11][C:10]=1[C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH3:37])[N:32]=[CH:31]2)C1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[OH:8][C:9]1[C:14]([NH:15][C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:11][C:10]=1[C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH3:37])[N:32]=[CH:31]2
Reactant: COC(=O)CCc1cc(NC(=O)C(F)(F)F)c(OCc2ccccc2)c(-c2ccc3c(cnn3C)c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCc1cc(NC(=O)C(F)(F)F)c(O)c(-c2ccc3c(cnn3C)c2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.2 %

Procedure:
A solution of Intermediate 56 (1.62 g) in a mixture of ethyl acetate (10 ml) and methanol (3 ml) was added with 10% palladium/carbon (29 mg), and stirred at room temperature for 17 hours under hydrogen atmosphere. The reaction mixture was filtered, and the solvent of the filtrate was evaporated under reduced pressure to obtain the title compound (Intermediate 57, 1.19 g).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][N:29]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[CH:31]=[N:30]1>>[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][N:29]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:2]3[C:3]4[C:10]5[CH2:11][CH2:12][NH:13][CH2:14][C:9]=5[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:35][CH:36]=2)[CH:31]=[N:30]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: Nc1ccc2c(cnn2Cc2ccccn2)c1
Product: c1ccc(Cn2ncc3cc(Nc4ncnc5sc6c(c45)CCNC6)ccc32)nc1

Procedure:
The title compound was synthesized in analogy to Example 12A from tert-butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (4.84 g, 14.5 mmol) and 1-(pyridin-2-ylmethyl)-1H-indazol-5-amine from Example 61A (3.50 g, 15.6 mmol) to yield 4.39 g (71%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:47])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]2[CH2:21][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:23](=[O:24])[C:19]=2[C:18]([O:33]C(C2C=CC=CC=2)C2C=CC=CC=2)=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2)[CH3:2].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].C([SiH](CC)CC)C>ClCCl>[CH2:1]([O:3][C:4](=[O:47])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]2[CH2:21][N:22]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:23](=[O:24])[C:19]=2[C:18]([OH:33])=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2)[CH3:2].[C:50]([OH:52])([C:49]([F:54])([F:53])[F:48])=[O:51]
Reactant: CCOC(=O)c1ccccc1-c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccccc1-c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 281 dissolved in dichloromethane (2 mL) was added trifluoroacetic acid (200 μl) and triethylsilane (400 μl). The reaction mixture was stirred at room temperature for ½ hours under an inert atmosphere then concentrated in vacuo. The residue was triturated with diethyl ether/hexane (1/1) to afford 2-[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl]-benzoic acid ethyl ester 282, TFA salt, (2.5 mg) as a yellow solid: 1H NMR (CD3OD) δ 8.9 (d, 1H), 8.0 (d, 1H), 8.0 (s, 1H), 7.8-7.6 (m, 3H), 7.5 (dd, 1H), 7.3 (m, 2H+1H), 7.0 (t, 2H), 4.7 (dd, 2H), 4.1 (dd, 2H), 3.7 (m, 2H), 0.6 (t, 3H); MS: 457 (M+1).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12]>C(O)(=O)C>[Br:1][CH2:12][C:11]([C:5]1[CH:6]=[CH:7][C:8]([I:10])=[CH:9][C:4]=1[F:3])=[O:13]
Reactant: CC(=O)c1ccc(I)cc1F
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(I)cc1F
Reaction time: 24 h
Yield: 99.2 %

Procedure:
A solution of bromine (2.74 mL, 53.18 mmol) in acetic acid (30 mL) was added dropwise to a solution of 1-(2-fluoro-4-iodo-phenyl)-ethanone (14.04 g, 53.18 mmol) in acetic acid (200 mL) at room temperature under an atmosphere of nitrogen and then stirred for 24 hours. The reaction was concentrated to near dryness in vacuo, diluted with ethyl acetate (200 mL) and basified with saturated aqueous sodium carbonate solution. The organic layer was washed with brine, dried over sodium sulfate, filtered through a pad of silica gel and concentrated in vacuo to give 2-bromo-1-(2-fluoro-4-iodo-phenyl)-ethanone (18.10 g, 99%).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:18].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][C:8](=[O:18])[N:7]2[CH2:6][CH:2]=[O:1])=[CH:12][CH:13]=1
Reactant: Cc1ccc2ccc(=O)n(CC3OCCO3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2ccc(=O)n(CC=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 0.37 g of 1-(1,3-dioxolan-2-ylmethyl)-7-methylquinolin-2(1H)-one, 3.7 mL of a 90% aqueous trifluoroacetic acid solution was added, the mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. The residue thus obtained was added with ethyl acetate and an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer and an extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.32 g of a brown oily substance, (7-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde.
Reaction SMILES: [CH2:1]([C@@H:8]([NH2:14])[CH:9]([O:12][CH3:13])[O:10][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:18]>C1(C)C=CC=CC=1>[CH2:1]([CH:8]([N:14]=[CH:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[OH:18])[CH:9]([O:10][CH3:11])[O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1O
Reactant: COC(OC)[C@H](N)Cc1ccccc1
Solvent: Cc1ccccc1
Product: COC(OC)C(Cc1ccccc1)N=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.8 %

Procedure:
In a 50 ml three-necked flask equipped with a thermometer, a magnetic stirrer and a condenser, 0.14 g of optically enriched (R)-1-benzyl-2,2-dimethoxyethylamine (91% ee, determined by chiral HPLC) (0.71 mmol, 1 mol.eq.) and 0.09 g of salicylaldehyde (0.71 mmol, 1 mol.eq.) are introduced into 1 g of toluene. This medium is left to stir at ambient temperature for 2-3 h. After concentrating, a crude mass of 0.21 g of 2-[(1-benzyl-2,2-dimethoxyethylimino)methyl]phenol is obtained.