Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH:17]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[C:21]=2[CH:20]=[CH:19][N:18]=1.CO.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH:17]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([S:27]([N:8]3[CH2:9][CH2:10][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][CH2:7]3)(=[O:29])=[O:28])[C:21]=2[CH:20]=[CH:19][N:18]=1
Reactant: CC(C)CN1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)CN1CCN(S(=O)(=O)c2cccc3cnccc23)CC1
Reaction time: 2 h
Yield: 78.1 %

Procedure:
In 30 ml of chloroform were added 1.42 g of 1-isobutylpiperazine and 2.76 g of potassium carbonate, and to the mixture was added dropwise 50 ml of a chloroform solution containing 2.28 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution thus obtained was stirred at a temperature of 15° C. to 25° C. for two hours, and then the reaction solution was washed with 20 ml of a 1N aqueous sodium hydroxide solution and extracted twice with a 5N aqueous hydrochloric acid solution. The aqueous hydrochloric acid layer was rendered alkaline, extracted three time with 30 ml of chloroform, and the chloroform layer extracted was washed with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom under reduced pressure, the residue obtained was subjected to a silica gel column chromatography (silica gel: 100 g; solvent: 2% methanol-chloroform) to give 2.60 g of 1-(5-isoquinolinesulfonyl)-4-isobutylpiperazine, i.e., Compound (47) in a yield of 78%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:25][CH:26]=1.C([Sn](CCCC)(CCCC)[C:38]([O:40]CC)=C)CCC.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:27]1([C:24]2[N:23]=[CH:22][C:21]([CH:38]=[O:40])=[CH:26][N:25]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Brc1cnc(-c2ccccc2)nc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: O=Cc1cnc(-c2ccccc2)nc1
Temperature: 80 °C
Yield: 36.4 %

Procedure:
A stirring mixture consisting of palladium(II) acetate (215 mg, 0.32 mmol) and triphenylphosphine (335 mg, 1.28 mmol) in 1,4-dioxane (25 mL) was heated at 80° C. for 30 minutes. The dark reaction mixture was cooled to room temperature, and to this reaction mixture was added a solution consisting of 5-bromo-2-phenylpyrimidine (Example 1A, 3.0 g, 13 mmol) and tributyl(1-ethoxyvinyl)tin (4.74 mL, 14.0 mmol) in 1,4-dioxane (63 mL). The reaction mixture was stirred and heated at 75° C. overnight and was subsequently cooled to room temperature. The reaction progress was monitored by thin layer chromatography (95:5 v/v hexanes-ethyl acetate) until completion. The reaction mixture was treated with 1 N hydrochloric acid (19 mL) for one hour at room temperature and poured into a saturated aqueous sodium bicarbonate solution. The organic material was extracted two times with a mixture of ethyl acetate and hexanes, and the combined organic phase was washed sequentially with water and brine, and was dried over anhydrous magnesium sulfate, filtered through a well packed pad of magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (30 mL) and diluted with hexanes (30 mL). The resulting precipitate was filtered to give the title intermediate (872 mg). The filtrate was applied to a 80-g silica column eluted with 1:1:9 v/v/v ethyl acetate-dichloromethane-hexanes to afford 1.01 g of additional title intermediate (1.88 g total, 74%); R1 0.23 with 9:1 v/v hexanes-ethyl acetate solvent system; 1H-NMR (400 MHz; DMSO-d6) δ 9.4 (s, 2H), 8.45-8.50 (m, 2H), 7.5-7.7 (m, 3H), 2.68 (s, 3H); MS (ESI+) m/z 199 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11][CH:12]=[CH2:13])=[C:9]([OH:14])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].I[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:35]=[CH:34][C:23]2[CH2:24][CH2:25][CH:26]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[O:27][C:22]=2[C:21]=1[CH2:36][CH2:37][CH3:38]>>[NH2:6][C:4]([C:3]1[CH:7]=[CH:8][C:9]([O:14][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:35]=[CH:34][C:23]3[CH2:24][CH2:25][CH:26]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[O:27][C:22]=3[C:21]=2[CH2:36][CH2:37][CH3:38])=[C:10]([CH2:11][CH:12]=[CH2:13])[C:2]=1[OH:1])=[O:5]
Reactant: CCCc1c(OCCCI)ccc2c1OC(CCC(=O)OC)CC2
Reactant: C=CCc1c(O)ccc(C(N)=O)c1O
Product: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(CCC(=O)OC)CC3)ccc(C(N)=O)c1O

Procedure:
The compound of Example 20 and the compound of Example 3 are coupled as described in Example 60. Chromatographic purification of the crude phenolic ester on silica gel using ethyl acetate/hexane (3:7) as eluant affords the product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH:16]([C:18]1[CH:19]=[N+:20]([O-])[CH:21]=[CH:22][CH:23]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:26][N:27](C)C(Cl)=O.C[Si](C#N)(C)C>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:26]#[N:27])=[N:20][CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CN(C)C(=O)Cl
Reactant: CC(c1ccc[n+]([O-])c1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: C[Si](C)(C)C#N
Solvent: ClCCl
Product: CC(c1ccc(C#N)nc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
A mixture of the product of part (i) (0.93 g) and N,N-dimethylcarbamoyl chloride (0.40 g) in dichloromethane (10 ml) was stirred at room temperature overnight. Trimethylsilyl cyanide (0.40 g) was added and stirring was continued for a further 60 hours. The solution was washed with 10% sodium carbonate solution and the aqueous layer was separated and washed with dichloromethane. The organic layers were combined, dried (MgSO4) and evaporated. The residue was chromatographed on silica gel using hexane/isopropanol (4:1) as eluant to give 2-(2,4-difluorophenyl)-3-(2-cyanopyridin-5-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, (0.18 g), m.p. 136°-141°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][C:12]=1[F:18].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:14]2[CH:15]=[CH:16][C:11]([F:10])=[C:12]([F:18])[CH:13]=2)[CH:7]=1
Reactant: Fc1ccc(I)cc1F
Reactant: C#Cc1cncc(Cl)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2cncc(Cl)c2)cc1F
Temperature: 60 °C
Yield: 85.5 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (49 mg, 0.07 mmol), copper (I) iodide (28 mg, 0.15 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (200 mg, 1.5 mmol) to a solution of 1,2-difluoro-4-iodobenzene (420 mg, 1.7 mmol) in triethylamine (3.1 mL, 22 mmol) and heat at 60° C. for 16 h. Cool to room temperature and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient of 50:50 to 100:0 dichloromethane:hexanes, followed by a second silica gel chromatography, eluting with 95:5 to 85:15 hexanes:ethyl acetate to give the title compound as a white solid (320 mg, 88%).
Reaction SMILES: [OH:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10]O)=[CH:7][CH:6]=1)[CH3:3].[ClH:12].[NH2:13][CH2:14][CH2:15][SH:16]>Cl>[ClH:12].[ClH:12].[NH2:13][CH2:14][CH2:15][S:16][CH2:10][C:8]1[O:9][C:5]([CH2:4][N:2]([OH:1])[CH3:3])=[CH:6][CH:7]=1
Reactant: NCCS
Reactant: CN(O)Cc1ccc(CO)o1
Agent: Cl
Product: CN(O)Cc1ccc(CSCCN)o1
Yield: 125.9 %

Procedure:
5-[[Hydroxy(methyl)amino]methyl]-2-furanmethanol (7.85 g) was added to a stirred solution of 2-aminoethanethiol hydrochloride (5.68 g) in concentrated hydrochloric acid (15 ml) at 0° during 45 mins. After 48 hr at 0° the crystalline solid which separated was mixed with isopropanol (40 ml), filtered and crystallised from ethanol to give the title compound (9.1 g) m.. 164°-165° dec.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[N:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:33]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:34])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)N3CCOCC3)ccc2C)cc1

Procedure:
A stirred solution of 5′-amino-2′-methyl-biphenyl-4-carboxylic acid ethyl ester (520 mg) in dry THF (25 ml) containing triethylamine (0.57 ml) was treated with 4-morpholine-carbonyl chloride (0.26 ml). After 18 h. the mixture was partitioned between water and dichloromethane. The dried extracts were evaporated and the residue purified on silica gel. Elution with ethyl acetate:petrol 1:1 gave the title compound as a yellow oil (416 mg).
Reaction SMILES: [C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:14][CH2:15][C:16]1(O)[CH:23]2[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:25][CH:17]1[CH2:18]3)[CH2:22]2>C1(C)C=CC=CC=1>[C:1]12([NH:14][CH2:15][C:16]3([CH:23]4[CH2:22][CH:21]5[CH2:20][CH:19]([CH2:18][CH:17]3[CH2:25]5)[CH2:24]4)[O:13]1)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: O=C1CCCCCCCCCCC1
Reactant: NCC1(O)C2CC3CC(C2)CC1C3
Solvent: Cc1ccccc1
Product: C1CCCCCC2(CCCCC1)NCC1(O2)C2CC3CC(C2)CC1C3

Procedure:
Cyclododecanone (0.91 gram, 5 mmol) was added to a solution of 2-aminomethyl-2-hydroxyadamantane (0.90 gram, 5 mmol) in 30 ml toluene. After the mixture was refluxed (Dean-Stark separator) for 7 hours, the solvent was evaporated leaving derivative VIII as a brown oil which crystallized from isopropanol, Yield--1.08 gram melting point 241°-245° C. (white crystals from isopropanol).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:54]=[CH:53][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH:50]([F:52])[F:51])[CH2:45][CH2:44]2)=[O:41])=[CH:38][C:37]=1[O:55][CH3:56]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:54]=[CH:53][C:39]([C:40]([NH:42][CH:43]5[CH2:48][CH2:47][N:46]([CH2:49][CH:50]([F:51])[F:52])[CH2:45][CH2:44]5)=[O:41])=[CH:38][C:37]=4[O:55][CH3:56])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NC2CCN(CC(F)F)CC2)ccc1N
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(CC(F)F)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Yield: 60.3 %

Procedure:
A mixture of 0.10 g (0.30 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.086 g (0.45 mmole) of toluenesulfonic acid monohydrate, 0.095 g (0.30 mmole) of 4-amino-N-[1-(2,2-difluoro-ethyl)-piperidin-4-yl]-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 170 degrees in a microwave reactor for 2 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from acetonitrile to give 0.110 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-[1-(2,2-difluoro-ethyl)-piperidin-4-yl]-3-methoxy-benzamide (I-266)
Reaction SMILES: Br[C:2]1[CH:37]=[CH:36][C:5]2[N:6]([C:9]3[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([O:18][C@@H:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][Si](C(C)(C)C)(C)C)[C:22]=4[Cl:35])[CH3:20])[CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:38][C:39]1[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41][N:40]=1>>[Cl:35][C:22]1[C:23]([OH:27])=[CH:24][CH:25]=[CH:26][C:21]=1[C@H:19]([O:18][C:11]1[CH:10]=[C:9]([N:6]2[C:5]3[CH:36]=[CH:37][C:2]([C:43]4[CH:42]=[CH:41][N:40]=[C:39]([CH3:38])[CH:44]=4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[S:13][C:12]=1[C:14]([O:16][CH3:17])=[O:15])[CH3:20]
Reactant: COC(=O)c1sc(-n2cnc3cc(Br)ccc32)cc1O[C@H](C)c1cccc(O[Si](C)(C)C(C)(C)C)c1Cl
Reactant: Cc1cc(B(O)O)ccn1
Product: COC(=O)c1sc(-n2cnc3cc(-c4ccnc(C)c4)ccc32)cc1O[C@H](C)c1cccc(O)c1Cl
Yield: 37.9 %

Procedure:
Methyl 5-(5-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate (Intermediate 8, 400 mg, 0.64 mmol) and (2-methyl-4-pyridinyl)boronic acid (105 mg, 0.77 mmol) were coupled using a procedure analogous to Intermediate 9 to give the title compound (126 mg, 38%). 1H NMR (400 MHz, d6-DMSO) δ 8.54 (s, 1H), 8.09 (s, 1H), 7.62-7.22 (m, 8H), 7.03 (dd, J=6.9, 2.5 Hz, 1H), 6.69 (s, 1H) 5.77 (q, J=6.4 Hz, 1H), 3.93 (s, 3H), 2.64 (s, 3H), 1.77 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](C(N)=O)=[C:6]2SC1C=CC=CC=1)=[O:2].CO.[CH2:24](Cl)Cl>>[CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:24])[CH:7]=[CH:6]2)=[O:2]
Reactant: ClCCl
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Solvent: CO
Product: Cn1ccc2cc(C=O)ccc21

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph; 400 mg, 1.35 mmol) with Mel (101 μl) as described in General Procedure XIV to provide the 5-formyl-1-methylindole the title compound 14 (280 mg, 67%), Rf (5% MeOH/CH2Cl2)=0.75.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:9][C:10]([NH2:13])=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>N1C=CC=CC=1.O>[N:1]1([CH2:7][C:8]2[S:9][C:10]([NH:13][CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cnc(CN2CCOCC2)s1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C(=CNc1cnc(CN2CCOCC2)s1)C(=O)OCC
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 2-(morpholin-4-ylmethyl)-1,3-thiazol-5-amine (Preparation 27, 1.13 g) in pyridine (10 mL) at 45° C. is added diethyl ethoxymethylenemalonate (2.26 mL). The mixture is stirred overnight, diluted with water (100 mL), and extracted with EtOAc (3×75 mL). The organic layer is dried (MgSO4) and the solvent removed. The residue is purified by column chromatography (eluent 50% EtOAc/hexane) to afford 1.51 g (86%) of the title compound as a brown oil. Physical characteristics: 1H NMR (CDCl3) δ1.27-1.37, 2.58, 3.72, 3.73, 4.20-4.30, 8.10, 11.02; IR (diffuse reflectance) 1687, 1637, 1596, 1416, 1337, 1301, 1274, 1268, 1243, 1234, 1114, 1094, 1011, 867, 801 cm−1; HRMS (FAB) m/z 370.1420 (C16H23N3O5S+H). Anal. Found: C, 51.80; H, 6.32; N, 11.26.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12]([OH:14])=O)=[C:5]([F:15])[CH:4]=1)#[N:2].[ClH:16].[N:17]1(C(=O)CC2C=NC(N3C=NN=N3)=CC=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[ClH:16].[F:15][C:5]1[C:6]([CH2:11][C:12](=[O:14])[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:7][C:8]([O:9][CH3:10])=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: O=C(Cc1ccc(-n2cnnn2)nc1)N1CCNCC1
Reactant: COc1cc(CC(=O)O)c(F)cc1C#N
Agent: Cl
Product: COc1cc(CC(=O)N2CCNCC2)c(F)cc1C#N

Procedure:
5-Fluoro-2-methoxy-4-[2-oxo-2-(piperazin-1-yl)ethyl]benzonitrile hydrochloride was prepared in two steps from (4-cyano-2-fluoro-5-methoxyphenyl) acetic acid in an analogous fashion to that described for the synthesis of 1-(piperazin-1-yl)-2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethanone hydrochloride. MS m/z 278 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH2:16][C:13]3([CH2:15][CH2:14]3)[CH2:12][CH:11]2[C:17]([O:19]CC)=[O:18])=[CH:4][CH:3]=1.COCCOC.[OH-].[Li+].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][CH:10]2[CH2:16][C:13]3([CH2:14][CH2:15]3)[CH2:12][CH:11]2[C:17]([OH:19])=[O:18])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CC2(CC2)CC1CSc1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Solvent: O
Product: O=C(O)C1CC2(CC2)CC1CSc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of ethyl(5R/S,6R/S)-6-{[(4 fluorophenyl)sulfanyl]methyl}spiro[2.4]-heptane-5-carboxylate (66 mg, 0.22 mmol) in 0.3 mL methanol was added ethylene glycol dimethyl ether (1.0 mL) and 2 M aqueous solution of lithium hydroxide (1.0 mL). The reaction mixture was stirred at ambient temperature for 22 h and then poured into 30 mL water. The reaction mixture was washed with 30 mL ether and the aqueous layer was acidified with a 2 M aqueous solution of hydrochloric acid. The product was extracted into ethyl acetate and the combined ethyl acetate extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give (5R/S,6R/S)-6-{[(4-fluorophenyl)sulfanyl]-methyl}spiro[2.4]heptane-5-carboxylic acid as a colorless syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][C:12]3[CH:14]=[N:15][C:16]([N:18](OC)[CH3:19])=[CH:17][C:11]=3[N:10]([CH3:22])[C:9]2=[O:23])=[CH:4][C:3]=1[N+:24]([O-])=O>CO.[Pd]>[NH2:24][C:3]1[CH:4]=[C:5]([N:8]2[CH2:13][C:12]3[CH:14]=[N:15][C:16]([NH:18][CH3:19])=[CH:17][C:11]=3[N:10]([CH3:22])[C:9]2=[O:23])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CON(C)c1cc2c(cn1)CN(c1ccc(F)c([N+](=O)[O-])c1)C(=O)N2C
Agent: [Pd]
Solvent: CO
Product: CNc1cc2c(cn1)CN(c1ccc(F)c(N)c1)C(=O)N2C
Yield: 66.4 %

Procedure:
A solution 3-(4-fluoro-3-nitrophenyl)-7-(methoxy(methyl)amino)-1-methyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (2 g, 5.5 mmol) in methanol (30 mL) was stirred with 10% Pd/C (1.0 g, 0.94 mmol) under hydrogen (45 psi) at 45° C. for 24 h. The complete reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was washed with ethyl ether and dried in vacuo to provide 3-(3-amino-4-fluorophenyl)-1-methyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (1.1 g, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.70 (s, 1 H), 6.94 (t, J=9.6 Hz, 1 H), 6.66 (d, J=6.8 Hz, 1 H), 6.40 (m, 2H), 5.92 (s, 1 H), 5.17 (s, 2 H), 4.50 (s, 2 H), 3.13 (s, 3 H), 2.73 (d, J=4.0 Hz, 3 H), MS (ESI) m/z: 302.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10][CH3:11])=[C:5]([CH3:12])[C:4]=1[CH3:13].[Br:14]Br>C(O)(=O)C>[Br:14][C:8]1[C:7]([CH3:9])=[C:6]([O:10][CH3:11])[C:5]([CH3:12])=[C:4]([CH3:13])[C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C)c(OC)c(C)c1C
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1c(C)c(C)c(OC)c(Br)c1C
Temperature: 0 °C
Yield: 83.6 %

Procedure:
A stirred solution of 1,4-dimethoxy-2,3,5-trimethylbenzene (61.2 g) was dissolved into 350 mL acetic acid (1.0 M) and treated with a solution of Br2 (17.7 mL, 55.1 g,) in 115 mL acetic acid over 1 h. The reaction was stirred for an additional hour and poured over 1.5 l ice. The cloudy solution was filtered and the solids washed 2×200 mL H2O and dried under high vacuum. The product was azeotroped twice from toluene to remove residual acetic acid to give 73.6 g of 1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene as a red-brown solid.; Mp 57.2-62.8° C.; 1H NMR (400 MHz, CDCl3) δ=3.75 (s, 3 H), 3.66 (s, 3 H), 2.35 (s, 3 H), 2.22 (s, 3H), 2.17 (s, 3H) ppm.
Reaction SMILES: [NH2:1][CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:3]([NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:29]1([N:35]=[C:36]=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>ClCCl>[CH:29]1([NH:35][C:36]([NH:1][CH:2]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:12])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C=NC1CCCCC1
Reactant: NC(c1ccccc1)C(NC(=O)Nc1ccc([N+](=O)[O-])cc1)c1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)NC(c1ccccc1)C(NC(=O)NC1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [R-(R*,R*)] and [S-(R*,R*)]N-(2-amino-1,2-diphenylethyl)-N'-(4-nitrophenyl)urea (0.1 g, 0.27 mmol) in dichloromethane (10 mL) is added cyclohexyl isocyanate (0.03 g, 0.27 mmol) in one portion. The resulting mixture is stirred 1 hour at room temperature before filtering off the solid product. The product is suspended in hot diethyl ether, filtered, and dried in vacuo at 114° C. for 4 hours, mp 244°-245° C. IR (KBr): 3337, 2931, 1639, 1559, 1507, 1330, 700 cm-1 ; NMR (DMS-d6): 0.97-1.66 (m, 10H), 4.94 (m, 2H), 5.94 (d, 1H, J=7.5 Hz), 6.42 (d, 1H, J=7.5 Hz), 7.03-7.19 (m, 12H), 7.60 (d, 2H, J=9.2 Hz), 8.12 (d, 2H, J=9.2 Hz), 9.51 (s, 1H). Analysis calculated for C 28 H31N5O4 : C, 67.05; H, 6.23; N, 13.96. Found: C, 66.74; H, 6.22; N, 13.98.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([O:13][CH3:14])[C:5]=1[O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([CH3:24])[C:17]=1[C:25]([OH:27])=[O:26].[CH3:29][O:30]C(Cl)Cl.Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([O:13][CH3:14])[C:5]=1[O:15][C:16]1[C:21]([CH:29]=[O:30])=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([CH3:24])[C:17]=1[C:25]([OH:27])=[O:26]
Reactant: COC(=O)c1cc(OC)c(C)c(OC)c1Oc1cc(OC)cc(C)c1C(=O)O
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cc(OC)c(C)c(OC)c1Oc1c(C=O)c(OC)cc(C)c1C(=O)O
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
2-(3-methyl-2-carboxy-5-methoxy-phenoxy)-3,5-dimethoxy-4-methyl-benzoic acid methyl ester (1 mmol) and dichloromethyl methyl ether (2 mmol) were taken in anhydrous dichloromethane (2 ml). The mixture was stirred and cooled to −10° C. in an ice-salt bath. Titanium tetrachloride (2.5 mmol) in dichloromethane (0.5 ml) was then added dropwise over 0.5 h. Stirring was continued for a further 1.5 h at −10° C. and then for 1.5 h at room temperature. To the reaction mixture was then added cold, dilute hydrochloric acid, and the reaction mixture was extracted with dichloromethane. The organic layer was washed with water, brine and then dried (MgSO4). The solvent was evaporated by a rotary evaporator and the residue was purified by column chromatography to afford 2-(3-methyl-6-Formyl-2-carboxy-5-methoxy-phenoxy)-3,5-dimethoxy-4-methyl-benzoic acid methyl ester (63%).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH2:6][CH:5]1[CH:4]1[C:9]([O:11][C:12](=[O:13])[CH:2]2[CH2:3]1)=O.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[N:29][CH:28]=[C:27]([Cl:31])[N:26]=2)[CH2:21][CH2:20]1>>[Cl:31][C:27]1[N:26]=[C:25]([N:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][CH2:15][N:14]3[C:12](=[O:13])[CH:2]4[CH2:3][CH:4]([CH:5]5[CH2:6][CH2:7][CH2:8][CH:1]54)[C:9]3=[O:11])[CH2:24][CH2:23]2)[CH:30]=[N:29][CH:28]=1
Reactant: O=C1OC(=O)C2CC1C1CCCC21
Reactant: NCCCCN1CCN(c2cncc(Cl)n2)CC1
Product: O=C1C2CC(C(=O)N1CCCCN1CCN(c3cncc(Cl)n3)CC1)C1CCCC21

Procedure:
The title compound was prepared from 4.58 g (25.4 mmoles) of bicyclo[3.3.0]-octane-2,4-dicarboxylic anhydride and 7.10 g (26 mmoles) of 1-(4-aminobutyl)-4-(6-chloro-2-pyrazinyl)-piperazine following the procedure in Example 1. 7.24 g of the hydrochloride salt was isolated as the one-quarter hydrate, m.p. 223°-225° C.