Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1.[CH3:12][N:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16](=O)[O:15]C1=O.Cl>CCCCCC.O.O1CCCC1>[CH3:12][NH:13][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16](=[O:15])[CH2:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: Cc1nnn[nH]1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CNc1ccccc1C(=O)Cc1nnn[nH]1
Reaction time: 1 h

Procedure:
A solution of butyl lithium in hexane (1.6M, 67.5 ml) was added to a stirred mixture of 5-methyltetrazole (4.54 g), and dry tetrahydrofuran (200 ml) at 0°. After stirring for 1 hour, 1-methyl-1H-3,1-benzoxazine-2,4-dione (9.6 g) was added and stirring continued for 65 hours at room temperature. The mixture was poured into water (300 ml) and acidified with 5N hydrochloric acid (12 ml). The organic phase was separated and the aqueous phase was extracted with dichloromethane (2×200 ml). The organic phases were combined, dried over anhydrous magnesium sulphate, and evaporated. The resulting solid was triturated with dichloromethane:industrial methylated spirit 9:1 (200 ml). The solid product was collected and recrystallised from ethyl acetate to give the novel compound 1-(2-methylaminophenyl)-2-(1H-tetrazol-5-yl)ethanone, m.p. 199°-201°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:27])[C:15]([F:26])([F:25])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:27])[C:15]([F:25])([F:26])/[CH:16]=[CH:17]/[C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[CH:6][CH:7]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(F)(F)/C=C/c1ccc(F)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(F)(F)/C=C/c4ccc(F)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using (E)-1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-difluoro-4-(4-fluoro-phenyl)-but-3-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14]Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:9][NH2:10])[CH2:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: N#CCc1cccc(Cl)c1
Product: NCC1(c2cccc(Cl)c2)CCC1

Procedure:
(1-(3-Chlorophenyl)cyclobutyl)methylamine is prepared from (3-chlorophenyl)acetonitrile (3.79 g, 25 mmol) and 1,3-dibromopropane (7.57 g, 375 mmol) as described in Example 1 in 60% overall yield.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1.P([O-])(O)(O)=O.[Na+]>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH:11]([OH:12])[C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1cccc2ccccc12)c1ccc(F)cc1
Agent: O=P([O-])(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(c1ccc(F)cc1)C(O)c1cccc2ccccc12
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
0.72 g (18.9 mmol) of sodium borohydride was added in 4 portions to a solution of 7.2 g (18.9 mmol) of tert-butyl [1-(4-fluorophenyl)-2-naphthalen-1-yl-2-oxoethyl]carbamate in 75 ml of methanol at 0-5° C. The reaction mixture was stirred at 0-5° C. for 1 h and then poured into an aqueous sodium dihydrogen phosphate solution (80 g/l). Extraction twice with ethyl acetate was followed by drying on magnesium sulfate. Concentration resulted in 7.4 g of tert-butyl [1-(4-fluorophenyl)-2-hydroxy-2-naphthalen-1-ylethyl]carbamate (diastereoisomer mixture: 85/15) as a pale yellow oil (yield: quantitative). The substance was used without further purification for the next stage.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)[C:9]=1[CH3:25].Cl.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][N:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=[C:16]1[S:15][CH2:14][C:10]1[C:9]([CH3:25])=[C:8]([S:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][N:11]=1
Reactant: CN(C)CCCl
Reactant: Cc1c(SCc2ccco2)ccnc1CSc1nc2ccccc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cc1c(SCc2ccco2)ccnc1CSc1nc2ccccc2n1CCN(C)C
Yield: 74 %

Procedure:
2-{[[4-(2-Furylmethylthio)-3-methyl-2-pyridinyl]methyl]thio}-1H-benzimidazole is stirred with 2-dimethylamino-ethyl chloride hydrochloride (1.5 equivalents), potassium carbonate (5 equivalents) and potassium iodide (0.05 equivalents) in acetonitrile at 100° C. for 24 h, the mixture is filtered, the filtrate is concentrated on a rotary evaporator, water is added to the residue and the mixture is extracted with methylene chloride. The combined organic phases are washed with water, dried and concentrated. The residue is crystallized from methylene chloride/diisopropyl ether. The title compound is obtained as a colorless powder; m.p. 87-89° C.; yield: 74% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH:23]([Si:26]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[N:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[C:29]([CH:36]=[O:37])=[CH:28]1)([CH3:25])[CH3:24].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:36]([OH:37])[C:29]3[C:30]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[N:27]([Si:26]([CH:38]([CH3:40])[CH3:39])([CH:41]([CH3:43])[CH3:42])[CH:23]([CH3:24])[CH3:25])[CH:28]=3)=[CH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C=O)c2cccnc21
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccc(Br)cn1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(C(=O)Nc3ccc(Cl)cc3)nc2)c2cccnc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 14.4 %

Procedure:
To 5-Bromo-pyridine-2-carboxylic acid (4-chloro-phenyl)-amide (70, 0.50 g, 1.60 mmol) in tetrahydrofuran (20.0 mL), under an atmosphere of nitrogen at −78° C., tert-butyllithium (3.02 mL, 1.70 M in Hexane) was added. After 20 minutes, 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (47, 0.39 g, 1.3 mmol, prepared as described in Example 18) in tetrahydrofuran (10.0 mL) was added to the reaction. The reaction was stirred at −78° C. for 1 hour, then allowed to warm to room temperature for 10 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound as colorless oil (71, 100 mg, 14%). MS (ESI) [M+H+]+=535.3.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CS(C)=O>[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=4)[C:12]#[N:13])=[CH:4][CH:3]=3)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)[nH]c1=O
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2ccc(N3CCN(c4ccccc4)CC3)cc2)[nH]c1=O

Procedure:
From 12.9 g. of 6-(p-fluorophenyl)-1,2-dihydro-2-oxonicotinonitrile and 19.5 g. of N-phenylpiperazine in 180 ml. of dimethyl sulfoxide, there is obtained 6-[p-(4-phenyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][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]([C:24](O)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:54][CH:53]1[CH2:61][NH2:62]>C(OCC)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[CH:27][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[CH2:19][CH2:20][CH:21]([C:24]([NH:62][CH2:61][CH:53]3[CH2:54][C:55]4[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=4)[CH2:52]3)=[O:25])[CH2:22][CH2:23]2)=[O:17])=[CH:4][CH:3]=1
Reactant: NCC1Cc2ccccc2C1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCC1Cc2ccccc2C1)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The following was added sequentially to DCM (8 mL): 1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (180 mg, 0.454 mmol), DIPEA (0.317 mL, 1.814 mmol), EDC (96 mg, 0.499 mmol), HOBT (76 mg, 0.499 mmol), and crude (2,3-dihydro-1H-inden-2-yl)methanamine (˜105 mg, 0.713 mmol). The mixture was stirred for 18 h at rt, at which time the solution diluted with a 1:1 solution of ethyl acetate:diethyl ether and washed with 1M HCl (1×), 10% aq. sodium carbonate (1×). The organic phase was dried with magnesium sulfate and concentrated in vacuo. Purification was accomplished via silica gel flash chromatography (60 g silica, 50% EtOAc/Hexanes), followed by EtOAc/hexane trituration to give the title compound as a white powder. (Yield: 137 mg, 0.260 mmol, 57%) 1H NMR (400 MHz, CDCl3) 7.66, 7.36-7.14, 7.04, 6.65, 5.55-5.40, 4.35, 3.39, 3.15-3.03, 2.88, 2.71-2.65, 2.31-2.19, 1.74, 1.49
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[C:13]([F:20])[CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:22][NH:23][O:24][CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.CCOC(C)=O.CCCCCCC>[F:20][C:13]1[CH:12]=[C:11]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[CH:19]=[CH:18][C:14]=1[C:15](=[O:17])[N:23]([O:24][CH3:25])[CH3:22]
Reactant: CNOC
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCCCCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1F
Yield: 91.9 %

Procedure:
A solution of (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-fluorobenzoic acid (1.416 g, 5 mmol), N,O-dimethylhydroxylamine hydrochloride (732 mg, 7.5 mmol), HATU (2.85 g, 7.5 mmol) and DIPEA (3.49 mL, 20 mmol) in DMF (25 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and washed with water. After separation, the aqueous phase was washed with EtOAc (2×75 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 12 to 100%) provided (S)-tert-butyl 1-(3-fluoro-4-(methoxy(methyl)carbamoyl)phenyl)ethylcarbamate as a white solid (1.5 g, 92% yield).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[N:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([N:47]3[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]3)[N:42]=2)[C:26]1=[O:54]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCCC1>[CH3:24][N:25]1[C:26](=[O:54])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([N:47]3[CH2:48][CH2:49][N:50]([CH3:53])[CH2:51][CH2:52]3)[N:42]=2)=[CH:28][C:29]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[CH2:22][CH2:21][N:13]4[C:14]5[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=5[CH:20]=[C:12]4[C:11]3=[O:23])[N:5]=[CH:4][CH:3]=2)=[CH:30]1
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CCN(c2cccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)n2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: CN1CCN(c2cccc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4C=O)cn(C)c3=O)n2)CC1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 4-chloro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino-[1,2-a]indol-2(1H)-yl)nicotinaldehyde 103b (377 mg, 1.15 mmol), 110a (320 mg, 0.78 mmol), Pd(dppf)Cl2 (130 mg, 0.16 mmol), K3PO4.3H2O (52.9 mg, 0.23 mmol), and tetrahydrofuran (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux overnight, cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (40:1) to afford 110b as yellow solid (351 mg, 76%). MS: [M+H]+ 593.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:23])=[C:15]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[CH:16]=3)[C:11](=[O:24])[N:10]([O:25]CC3C=CC=CC=3)[C:9]2=[O:33])[CH:5]=[CH:6][CH:7]=1>[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:23])=[C:15]([N:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)[CH:16]=3)[C:11](=[O:24])[N:10]([OH:25])[C:9]2=[O:33])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2cccc(F)c2)c(=O)n1OCc1ccccc1
Agent: [Pd]
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2cccc(F)c2)c(=O)n1O
Yield: 113.8 %

Procedure:
Using the General Method 6A, the reaction of 10% Pd/C (0.03 g) with 1-(3-fluorophenyl)-6-fluoro-3-benzyloxy-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione (Example Y-1, 0.1 g, 0.22 mmol) provided 0.09 g of the title compound as a solid, mp 239-241° C.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][S:5](=[O:19])(=[O:18])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=1.[OH-].[Na+]>O1CCOCC1>[F:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][S:5]([CH2:4][C:3]([OH:20])=[O:2])(=[O:18])=[O:19])=[CH:8][C:9]=1[C:14]([F:17])([F:15])[F:16]
Reactant: COC(=O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
12.79 g (40.57 mmol) of 2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]acetic acid methyl ester is dissolved in 110 ml of dioxane and combined with 59 ml (118 mmol) of 2N sodium hydroxide solution. The mixture heated up slightly, and the starting material had disappeared after 15 minutes. The mixture is concentrated to dryness under vacuum, the residue is combined with 2N hydrochloric acid, and the thus-precipitated acid is taken up in ethyl acetate. The organic solution is washed with water, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is crystallized from ethyl acetate/hexane. The title compound melts at 138°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH:23]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[CH2:22][CH2:21]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].C=O.[C:34]([BH3-])#N.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][CH:23]([CH:26]5[CH2:31][CH2:30][N:29]([CH3:34])[CH2:28][CH2:27]5)[CH2:22][CH2:21]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Nc2ncnc3cnc(N4CCC(C5CCNCC5)CC4)nc23)cc1Cl
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Product: CN1CCC(C2CCN(c3ncc4ncnc(Nc5ccc(F)c(Cl)c5)c4n3)CC2)CC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[4-(4-piperidinyl)-1-piperidinyl]pyrimido[5,4-d]pyrimidine by reductive amination with formaldehyde and sodium cyanoborohydride. Melting point: 159°-162° C.; Rf : 0.58 (alumina; petroleum ether/ethyl acetate/methanol=10:10:1)
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:13]([C:18]3[CH:26]=[C:25]([O:27][CH3:28])[C:21]4[O:22][CH2:23][O:24][C:20]=4[CH:19]=3)[C:14]([O:16][CH3:17])=[O:15])=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[C:29]1(C)C=CC(S(OC)(=O)=O)=CC=1>CN(C)C=O>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:13]([C:18]3[CH:26]=[C:25]([O:27][CH3:28])[C:21]4[O:22][CH2:23][O:24][C:20]=4[CH:19]=3)[C:14]([O:16][CH3:17])=[O:15])=[CH:9][N:10]2[CH3:29])=[CH:6][CH:5]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)C(c1cc(OC)c2c(c1)OCO2)c1c[nH]c2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1cc(OC)c2c(c1)OCO2)c1cn(C)c2cc(Br)ccc12
Reaction time: 0.5 h
Yield: 53 %

Procedure:
Sodium hydride (289 mg of a 60% dispersion in paraffin wax) was added in portions to a stirred solution of methyl 2-(6-bromo-1H-3-indolyl)-2-(7-methoxy-1,3-benzodioxol-5-yl)acetate (from step (c), 2.7 g, 6.5 mmol) in anhydrous dimethylformamide (20 ml) at 0° C. under a nitrogen atmosphere. After 30 minutes, methyl p-toluenesulphonate (1.34 g, 7.2 mmol) was added. After a further 1 hour the mixture was partitioned between diethyl ether and water. The organic layer was separated and washed twice with water. The organic layer was dried (magnesium sulphate) and the solvent was removed in vacuo. The residue was purified by flash column chromatography (using 30% hexane, 70% dichloromethane as eluant) to give 1.49 g of the subtitle compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Br.[NH2:19][CH:20]1[CH2:25][CH2:24][O:23][C:21]1=[O:22]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([CH:25]2[CH2:24][O:23][C:21](=[O:22])[CH:20]2[NH2:19])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1CCOC1=O
Agent: Br
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1COC(=O)C1N

Procedure:
Following General Procedure A above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and α-amino-γ-butyrolactone hydrobromide (Aldrich), the title compound was prepared as a solid having a melting point of 174-177° C. The reaction was monitored by tlc on silica gel (Rf=0.52 in 10% methanol/dichloromethane) and purification was by silica gel chromatography.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[C:6]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:15][N:16]([CH3:18])[CH:17]=2)[N:5]=1)[CH3:2].Cl[Sn]Cl>CCOC(C)=O>[CH2:1]([S:3][C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[C:6]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:15][N:16]([CH3:18])[CH:17]=2)[N:5]=1)[CH3:2]
Reactant: CCSc1nc(-c2cn(C)nc2-c2ccccc2F)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Product: CCSc1nc(-c2cn(C)nc2-c2ccccc2F)ccc1N
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A solution of 2-(ethylthio)-6-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-3-nitropyridine (2.87 g, 8.01 mmol, 1.00 eq.) and SnCl2●2H2O (9.05 g, 40.1 mmol, 5.0 eq.) in EtOAc (200 mL) was refluxed for 2 h. After cooling to room temperature, the solution was washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(ethylthio)-6-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyridine-3-amine as a yellow solid (2.31 g, 88% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22](=O)[O:23]CC(Cl)(Cl)Cl)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:31]([NH2:34])[CH2:32][CH3:33]>CCCCCC.C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22]([NH:34][CH2:31][CH2:32][CH3:33])=[O:23])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: CCCN
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCNC(=O)Nc1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Yield: 53 %

Procedure:
Using 2,2,2-trichloroethyl (3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and 1-propylamine, the title compound was synthesized in the same manner as in Example 143. Yield: 53%. Melting point: 177-178° C. (hexane-ethyl acetate).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH:9](OCC)=[O:10]>>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][CH:9]=[O:10])=[CH:4][CH:5]=1
Reactant: CCOC=O
Reactant: NCc1ccncc1
Product: O=CNCc1ccncc1
Reaction time: 16 h

Procedure:
A solution of 4-(aminomethyl)pyridine (54.1 g, 0.5 mol) and ethyl formate (44.4 ml) was refluxed for two hours and then permitted to stand at ambient temperature for 16 hours. The reaction was distilled to produce 61.6 g of N-(4-pyridylmethyl)formamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1CC#N.[C:18]([OH:21])(=[O:20])[CH3:19].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:19][C:18]([OH:21])=[O:20]
Reactant: CC(=O)O
Reactant: N#CCc1cccc(C(=O)c2cccs2)c1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1cccc(C(=O)c2cccs2)c1Cl
Reaction time: 1 h

Procedure:
A mixture of 4.2 parts of 2-[2-chloro-3-(2-thenoyl)phenyl]acetonitrile, 7 parts of acetic acid, 7 parts of water and 12 parts of sulfuric acid is stirred and boiled for 1h. 30. The reaction mixture is cooled, poured onto water and extracted with ether. The extract is washed with water, extracted with 50 parts of a 5% sodium hydroxide solution and the alkaline solution is washed with ether. After acidification with diluted hydrochloric acid solution, the whole is extracted again with ether. The extract is washed with water, treated with charcoal, filtered and evaporated. The residue is purified by column-chromatography over silicagel, using a mixture of chloroform and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 2-[2-chloro-3-(2-thenoyl)phenyl]acetic acid; mp. 112.2° C.
Reaction SMILES: [C:1](=[O:13])([S:11][CH3:12])[O:2][CH:3]([O:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])C.ClC(OCCl)=O.[CH:20]1(C(O)=O)[CH2:25]CCC[CH2:21]1>>[C:1](=[O:13])([S:11][CH3:12])[O:2][CH2:3][O:5][C:6]([CH:7]1[CH2:9][CH2:25][CH2:20][CH2:21][CH2:8]1)=[O:10]
Reactant: CSC(=O)OC(C)OC(=O)C(C)C
Reactant: O=C(O)C1CCCCC1
Agent: O=C(Cl)OCCl
Product: CSC(=O)OCOC(=O)C1CCCCC1

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyethyl) S-methyl thiocarbonate (2) and replacing 1-chloroethyl chloroformate with chloromethyl chloroformate in Step A and replacing isobutyric acid with cyclohexanecarboxylic acid in Step B affords O-(cyclohexanoyloxymethyl) S-methyl thiocarbonate (10) as an oil.