Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][N:7]=[CH:6]2.O=P(Cl)(Cl)[Cl:24]>C(Cl)Cl>[Cl:24][C:9]1[C:10]2[C:5](=[C:4]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[N:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]ncc2c1C#Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc2c(Cl)nncc2c1C#Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6-methoxy-5-phenylethynyl-2H-phthalazin-1-one (0.67 g, 2.42 mmoles), prepared as described in example 60, in POCl3 (20 ml) was heated at 80° C. under stirring up to dissolution. After 30 minutes the solution was brought to dryness and the residue taken up in CH2Cl2 (100 ml), washed to alkalinity with a solution of K2CO3, then with water, then anhydrified over Na2SO4 and evaporated to give 715 mg of the title compound (quantitative yield). The compound was used as such in the subsequent step.
Reaction SMILES: [C:1]([C:5]1([CH3:11])[CH:9]=[CH:8][CH:7]([CH3:10])[O:6]1)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([C:5]1([CH3:11])[CH2:9][CH2:8][CH:7]([CH3:10])[O:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C=CC(C)(C(C)(C)C)O1
Agent: [Pd]
Product: CC1CCC(C)(C(C)(C)C)O1
Yield: 85.1 %

Procedure:
According to the procedure of example 2, by hydrogenation of 1.62 g (10.3 mmol) of 2-tert-butyl-2,5-dimethyl-2,5-dihydrofuran in the presence of 600 mg (0.56 mmol) of 10% palladium on activated charcoal. Kugelrohr distillation furnished at 45-50° C./20 mbar 1.37 g (82%) of the title compound as a colorless odoriferous liquid.
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[CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.[CH3:24][O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.C(N(CC)CC)C>CS(C)=O>[CH3:24][O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:21]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:22])=[CH:31][CH:30]=1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Cl)CC3)c2cc1OC
Reactant: COCCOc1ccc(N)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COCCOc1ccc(NC(=O)N2CCC(c3ncnc4cc(OC)c(OC)cc34)CC2)cc1
Temperature: 25 °C
Yield: 22.9 %

Procedure:
A mixture of 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride (18 mg, 0.0536 mmol), as prepared in Example 3a, 4-(2-methoxy-ethoxy)-phenylamine (8.9 mg, 0.0533 mmol), as prepared in the previous step, and triethylamine (14 μL, 0.1 mmol) was stirred in DMSO (0.5 mL) at 50° C. overnight. The reaction was then cooled to RT, partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a brown solid (5.7 mg, 23%). 1H NMR (300 MHz, CDCl3) δ 9.16 (s, 1H), 7.28-7.25 (m, 4H), 6.89 (m, 2H), 6.33 (br s, NH), 4.29-4.24 (m, 2H), 4.12-4.07 (m, 8H), 3.74 (m, 2H), 3.59 (m, 1H), 3.45 (s, 3H), 3.17 (m, 2H), 2.22-2.08 (m, 2H), 2.05-1.97 (m, 2H); LC/MS (ESI): calcd mass 466.2, found 467.4 [M+1]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.Cl.[CH3:27][N:28]1[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29]1.CC(C)([O-])C.[Na+].CN(C=O)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:33][C:31]3[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Cn1cc(N)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Temperature: 140 °C
Yield: 57.3 %

Procedure:
To a mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 mol), 1-methyl-1H-pyrazol-4-amine hydrochloride (70.3 mg, 526 mol), BINAP (10.9 mg, 17.5 mol), palladium (II) acetate (19.7 mg, 87.7 mol) and sodium tert-butoxide (84.3 mg, 877 mol) was added DMF (1 mL) and toluene (500 μL). After heating in a microwave at 140° C. for 20 min, the reaction mixture was cooled, diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, then dried over magnesium sulfate, and purified by chromatography (silica, 30-70% ethyl acetate in hexanes) to give N-tert-butyl-2-(1-methyl-1H-pyrazol-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (89 mg, 201 mol, 57%) as a yellow solid. MS (EI/CI) m/z: 314.1 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH2:12])[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[C:14]([O-:24])(=[O:23])[C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16].O[C@@H](C1C=CC=CC=1)C(O)=O>C(OCC)(=O)C>[OH:16][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([O-:24])=[O:23].[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:7]2[CH2:13][C@@H:10]([CH2:9][CH2:8]2)[C@@H:11]1[NH3+:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Agent: O=C(O)[C@@H](O)c1ccccc1
Agent: O=C([O-])[C@@H](O)c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1[NH3+]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
In order to determine the enantiomeric excess, (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester was derivatized to the (S)-mandelate salt as follows: To a solution of (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (34.2 mg, 0.187 mmol) in ethyl acetate (1 mL) was added (S)-α-hydroxyphenylacetic acid (28.7 mg, 0.187 mmol) and the mixture was stirred at 25° C. for 0.5 h. The solid was filtered and dried under high vacuum to afford (1R,2S,3R,4S)-3-ethoxycarbonyl-bicyclo[2.2.1]hept-2-yl-aminium (S)-α-hydroxyphenylacetate (11.4 mg, 0.034 mmol, 18%, de=97%), as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.08-1.20 (3H, m), 1.28 (3H, t, J=7.1 Hz), 1.50-1.59 (2H, m), 1.79 (1H, d, J=10.9 Hz), 2.23 (1H, s), 2.46-2.48 (2H, m), 3.04 (1H, d, J=7.8 Hz), 4.05-4.18 (2H, m), 4.89 (1H, s), 5.49 (3H, bs), 7.22-7.31 (3H, m), 7.43 (2H, d, J=6.9 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:23][OH:24]>>[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:23][O:24][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cccc(F)c1F
Product: CN1c2cc(OCc3cccc(F)c3F)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (2,3difluorophenyl)methanol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH3:19]>C(O)(C)C>[NH2:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: N
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Solvent: CC(C)O
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1N
Temperature: 110 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of ethyl 4-chloro-6-methoxyquinoline-3-carboxylate (Example 1b, 796 mg, 3.0 mmol) and ammonia (25% aqueous solution, 10 mL) in isopropanol (40 mL) was stirred at 110° C. in a pressure reactor overnight. Most of the solvent was then removed under reduced pressure, and the reaction mixture was diluted with water. The precipitate was collected by filtration, washed with cold water, and dried under vacuum to give the title compound as an off-white solid (680 mg, 92%). 1H NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=7.0 Hz, 3H), 3.88 (s, 3H), 4.32 (q, J=7.0 Hz, 2H), 7.36 (dd, J=2.8, 8.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.74 (d, J=2.8 Hz, 1H), 8.23 (bs, 2H), 8.77 (s, 1H). MS 247 (MH+).
Reaction SMILES: C(OC(N1CCC(C([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.[H-].[Na+].[CH2:46]([O:48][C:49](=[O:61])[C:50](Br)([CH2:56][CH:57]1[CH2:59][CH2:58]1)[C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:47]>CN(C=O)C>[CH2:46]([O:48][C:49](=[O:61])[C:50]([CH2:56][CH:57]1[CH2:59][CH2:58]1)([O:20][C:21]1[CH:43]=[CH:42][C:24]2[C:25]3[N:29]([CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1)[CH:28]=[C:27]([C:33]1[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=1)[N:26]=3)[C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:47]
Reactant: CCOC(=O)C(Br)(CC1CC1)C(=O)OCC
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1CC1)(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 187.2 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (100 mg, 0.307 mmol) in DMF (2 mL) was added sodium hydride (12.3 mg, 60% in oil, 0.307 mmol). The mixture was stirred at RT for 15 min, then 2-bromo-2-cyclopropylmethylmalonic acid diethyl ester (135 mg, 0.46 mmol) was added. The reaction mixture was stirred at RT for 1 h, and then at 70° C. for 6 h. The reaction was repeated with 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (400 mg, 1.23 mmol), DMF (8 mL), sodium hydride (49.2 mg, 1.23 mmol) and 2-bromo-2-cyclopropylmethylmalonic acid diethyl ester (540 mg, 1.84 mmol). The cooled reaction mixtures were combined and partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-10% MeOH in DCM) affording the title compound (0.309 g, 37%). LCMS (Method B): RT 3.77 min [M+H]+ 538.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[O:10][CH:11]=[CH:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[CH:12]=[CH:11][O:10][C:5]2=3)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: CN1CCC(O)c2occc2C1
Product: CN1CCC(Oc2ccc(Cl)c(Cl)c2)c2occc2C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-5,6,7,8-tetrahydro-4H-furo[3,2-c]azepin-8-ol (Reference Example 21) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C@@H:7]2[CH2:10][C@H:9]([C:11](OCC)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.Cl>C(Cl)Cl>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C@@H:7]2[CH2:10][C@H:9]([CH:11]=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@H]1C[C@@H](Oc2ccc(F)cc2)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: O=C[C@H]1C[C@@H](Oc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
To a solution of ethyl cis-3-(4-fluorophenoxy)cyclobutanecarboxylate (5.07 g, 21.3 mmol) in dry methylene chloride (100 ml) cooled to -78° C. was added dropwise diisobutylaluminum hydride (23.7 ml, 22.0 mmol, 0.93M in hexane) under an argon atmosphere. After completion of addition, the mixture was stirred at the same temperature for 0.5 h. Methanol (5 ml) was carefully added to the reaction mixture at -78° C. and the whole allowed to warm to room temperature over 1 h. 2N aqueous hydrochloric acid (200 ml) was added, the whole extracted with ethyl acetate (300 ml) and the combined extracts washed with brine (200 ml). The organic layer was dried (MgSO4) and concentrated in vacuo. Chromatographic purification of the residue {SiO2, 300 g; hexane/ethyl acetate (4:1)} provided 3.20 g (78%) of title compound as a colorless oil: 1H NMR δ9.73 (d, J=2.6 Hz, 1H), 7.03-6.91 (m, 2H), 6.80-6.70 (m, 2H), 4.72-4.59 (m, 1H), 2.97-2.83 (m, 1H), 2.75-2.61 (m, 2H), 2.48-2.33 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=O)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH2:17][NH2:18].CC(O)=O>C(O)C>[Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=[N:17][NH2:18])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(c1c(Cl)cnc2[nH]ccc12)C1CCC1
Reactant: NN
Solvent: CC(=O)O
Solvent: CCO
Product: NN=C(c1c(Cl)cnc2[nH]ccc12)C1CCC1
Yield: 47.3 %

Procedure:
A mixture of (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclobutyl)methanone (0.2 g, 0.85 mmol), anhydrous hydrazine (0.13 mL, 4.26 mmol) and AcOH (0.008 mL, 0.142 mmol) in ethanol (10 mL) was heated at reflux for about 20 h. During this time, water was distilled from the reaction mixture via the use of a Dean-Stark trap. The volatiles were removed under reduced pressure and the residue was partitioned between water (10 mL) and EtOAc (20 mL). The organic phase was dried over anhydrous MgSO4, filtered, and the solvent evaporated under reduced pressure. The crude material was purified by chromatography over silica gel using a 10 to 50% gradient of EtOAc in heptane as the eluent to provide 5-chloro-4-(cyclobutyl(hydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine as an off-white solid (0.10 g, 49%): LC/MS (Table 2, Method o) Rt=2.22 min; m/z: 249 and 251 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]([F:35])([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=2)=[CH:24][CH:23]=1)[C:4]([C:6]1[N:7](S(N(C)C)(=O)=O)[CH:8]=[C:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:10]=1)=[O:5].C[OH:37]>>[CH3:14][C:12]([CH3:13])([CH3:15])[CH2:11][C:9]1[N:10]=[C:6]([C:4]([OH:5])([OH:37])[C:3]([F:2])([F:35])[C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)=[CH:26][CH:27]=2)[NH:7][CH:8]=1
Reactant: CO
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)C(F)(F)c1ccc(-c2ccc(F)cn2)cc1
Agent: Cl
Product: CC(C)(C)Cc1c[nH]c(C(O)(O)C(F)(F)c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (1 mL, 4 mmol) was added to an ambient temperature solution of 2-{difluoro[4-(5-fluoropyridin-2-yl)phenyl]acetyl}-4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (20 mg, 0.04 mmol) in methanol (2 mL). After stirring at 70° C. for 1 h, volatiles were removed. The residue was partitioned between ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded the title compound. LCMS: 406 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:24][CH2:25][CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)=[O:23])=[C:15]3[N:14]=2)=[CH:6][C:5]([F:36])=[CH:4][N:3]=1.Cl>>[NH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:22]([C:21]1[CH:20]=[N:19][N:16]2[CH:17]=[CH:18][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[C:7]3[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([F:36])[CH:6]=3)=[N:14][C:15]=12)=[O:23]
Reactant: CC(C)(C)OC(=O)NCCCNC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3Cl)nc12
Agent: Cl
Product: NCCCNC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3Cl)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (R)-tert-butyl 3-(5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)propylcarbamate (Example 222, 6 mg, 0.012 mmol) and HCl (4 N dioxane, 145 μL, 0.58 mmol) was stirred at ambient temperature for 2 hours and concentrated to yield the product as white solid. LCMS (apci pos) m/z=418.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([OH:35])=[CH:30][C:29]=3[CH3:36])[CH:25]=[CH:26][CH:27]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].[CH2:46]([NH:48][CH2:49][CH2:50]O)[CH3:47].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:46]([NH:48][CH2:49][CH2:50][O:35][C:31]1[CH:32]=[C:33]([CH3:34])[C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][N:8]([S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:6]3[CH:5]=[CH:4][C:3]([CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[C:2]([F:1])[CH:7]=3)[CH:23]=2)=[C:29]([CH3:36])[CH:30]=1)[CH3:47]
Reactant: CCNCCO
Reactant: Cc1cc(O)cc(C)c1-c1cccc(CN(c2ccc(CCC(=O)OC(C)(C)C)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCNCCOc1cc(C)c(-c2cccc(CN(c3ccc(CCC(=O)OC(C)(C)C)c(F)c3)S(=O)(=O)c3ccccc3[N+](=O)[O-])c2)c(C)c1
Temperature: 25 °C
Yield: 152.7 %

Procedure:
To a solution of tert-butyl 3-(2-fluoro-4-{[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methyl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (3.60 g, 5.67 mmol), 2-(ethylamino)ethanol (0.61 mL, 6.24 mmol) and tributylphosphine (2.26 mL, 8.51 mmol) in tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (2.21 g, 8.53 mmol) under stirring at room temperature, and the mixture was stirred for 16 hr. The resulting precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=5/1-hexane/ethyl acetate=1/3) to give a mixture (6.11 g) of tert-butyl 3-(4-{({4′-[2-(ethylamino)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)[(2-nitrophenyl)sulfonyl]amino}-2-fluorophenyl)propanoate and tributylphosphine oxide as a yellow oil. To a solution of the obtained oil (0.57 g) in pyridine (3 mL) were added 2-methylpropanoyl chloride (0.17 mL, 1.62 mmol) and a small amount of N,N-dimethylpyridine-4-amine under stirring at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/5) to give the title compound (0.35 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH:16]=[C:5]1[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]1=[O:9])[CH3:15]
Reactant: COC(OC)N(C)C
Reactant: CC1(C)CC(=O)CC(=O)C1
Product: CN(C)C=C1C(=O)CC(C)(C)CC1=O
Yield: 46 %

Procedure:
According to Scheme 2 Step 1: A solution of 5,5-dimethylcyclohexane-1,3-dione (428 mmol, 60 g) and of 1,1-dimethoxy-N,N-dimethylmethanamine (514 mmol, 68.2 mL) was stirred at room temperature for 1 hour. After evaporation and trituration in cyclohexane, 38.5 g (197 mmol, 46%) of 2-((dimethylamino)methylene)-5,5-dimethylcyclohexane-1,3-dione were obtained as a pale yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=2)[NH2:9])=[CH:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][S:23][CH2:24][C:25](O)=[O:26])=[C:16]([C:29]([O:31]C)=[O:30])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][S:23][CH2:24][C:25]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:7]=2)=[O:26])=[C:16]([CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: Nc1cccc(-c2ccoc2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Product: O=C(CSCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccoc2)c1

Procedure:
Using the same method as in Example 15-(ii), 3-(furan-3-yl)aniline was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid obtained in Example 12-(i) to give 5-chloro-2-(([(2-([3-(furan-3-yl)phenyl]amino)-2-oxoethyl)sulfanyl]acetyl)amino)benzoic acid.methyl ester (yield: 65%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[Mg+2:10].[N+]([O-])([O-])=O.[OH-].[Al+3].[OH-].[OH-].S([O-])([O-])(=O)=O.[Al+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Al+3]>O>[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[Mg+2:10].[NH2:1][CH2:2][C:3]([O-:5])=[O:4]
Reactant: NCC(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: NCC(=O)[O-]
Temperature: 75 °C

Procedure:
Magnesium glycinate was prepared by reacting 5 grams of glycine with 3.1 grams of basic magnesium carbonate (26.3% Mg) in 15 grams of water. The mixture was heated at 75° C. for 1/2 hour with agitation. The hot solution was then added to 113 grams of zirconyl nitrate (7.9% Zr) with stirring. After the addition of 1.5 grams of aluminum hydroxide powder (28.8% Al), the mixture was reacted with agitation at 75° C. for 1/2 hour. To the resultant clear solution was added 7.9 grams of 2/3 basic aluminum sulfate, Al(OH)2SO4 (3.1% Al). The solution was then oven dried at 58° C. under a vacuum of 328 mm of Hg. The product contained 1.2% Mg, 13.2% glycine, 1.5% Al, 24.3% Zr, 4.02% SO4 and 29.5% nitrate.
Reaction SMILES: C([O-])(=O)C(C(C([O-])=O)O)[OH:3].[NH2:11][CH2:12][CH:13]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:14][C:15](N(CC)CC)=[O:16].[OH-].[Na+].[OH-].[K+].Cl>O.ClCCl>[CH3:24][CH:23]([CH2:22][C@H:13]([CH2:12][NH2:11])[CH2:14][C:15]([OH:16])=[O:3])[CH3:25]
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: CCN(CC)C(=O)CC(CN)CC(C)C
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 22.5 °C
Reaction time: 0.21 h

Procedure:
The tartarate salt of 3-aminomethyl N,N-diethyl-5-methyl hexanamide (10 grams) was dissolved in water (15 ml) and dichloromethane (25 ml) was added to it. The pH of reaction mixture was adjusted to 9-10 by addition of sodium hydroxide solution (3.0 gm NaOH in 3.0 ml of water) and stirred for 10-15 min at 20-25° C. The aqueous and organic layers were separated. The aqueous layer was extracted with dichloromethane. The aqueous layer was taken up for recovery of tartaric acid. The solvent was distilled off from combined organic layer to obtain a residue. Potassium hydroxide (5.0 grams) and water (5.0 ml) was added to the residue and heated to 115° C., the reaction was stirred at this temperature for 20 hours. The reaction mixture was cooled to 30° C. and the pH adjusted to 4.0 using concentrated hydrochloric acid. The reaction mixture was heated to 80° C. and stirred for 45 min and filtered. The filtrate was cooled to 5° C. and stirred for ninety minutes. The precipitated solid was filtered and washed with cool water. The solid was dried at 50-55° C. to yield (S)-Pregabalin.