Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:23](OC(ON=C(C#N)C(OCC)=O)=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCOCC1>[CH2:23]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(C#N)=NOC(=O)OCc1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(CNC(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of N-benzyloxycarbonylglycine (0.42 g) and triethylamine (0.28 ml) in dioxane (5 ml), ethyl 2-benzyloxycarbonyloxyimino-2-cyanoacetate (0.55 g) is added, and the resulting mixture is stirred for 3 hours. The reaction mixture is treated as in Example A to give N-benzyloxycarbonylglycine benzyl ester (0.57 g) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:16][NH:17][CH3:18]>C(O)C>[CH3:16][N:17]([CH3:18])[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: O=CN1CCN(c2ccnc(Cl)n2)CC1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1nccc(N2CCN(C=O)CC2)n1

Procedure:
2-Chloro-4-(4-formylpiperazino)pyrimidine (5.0 g) and dimethylamine (7.8 ml, 33% solution in ethanol) in ethanol (70 ml) were heated under reflux for 8 hours. The solvent was evaporated in vacuo and the residue was partitioned between chloroform and water. The aqueous layer was extracted twice with chloroform and the combined chloroform layers dried (Na2SO4) and evaporated in vacuo. The residue was re-crystallized from ethyl acetate to give 2-dimethylamino-4-(4-formylpiperazino)pyrimidine (2.7 g), m.p. 116° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[F:31][C:32]([F:41])([F:40])[C:33]1[N:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1.CN1CCOCC1>ClCCl.CN(C)C=O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:39][C:36]3[CH:37]=[N:38][C:33]([C:32]([F:41])([F:31])[F:40])=[CH:34][CH:35]=3)=[O:16])[C:9]2=[O:17])=[CH:19][CH:20]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)Nc1ccc(C(F)(F)F)nc1
Reaction time: 1 h

Procedure:
To a suspension of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.255 g, 0.771 mmol; Example 58D) in dichloromethane (3 mL) was added a catalytic amount of N,N-dimethylformamide followed by oxalyl dichloride (2.0 Min dichloromethane) (0.617 mL, 1.234 mmol). The reaction was stirred for 1 hour, after which a reddish solution resulted. The reaction was concentrated and dried under high vacuum. The residue was dissolved in dichloromethane (3 mL) and 6-(trifluoromethyl)pyridin-3-amine (0.100 g, 0.617 mmol) and 4-methylmorpholine (0.136 mL, 1.234 mmol) were added. After stirring for 1 hour, the reaction was loaded onto a GraceResolv™ 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 60% ethyl acetate/hexanes (Flow=40 mL/minute) over 40 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.51 (d, J=2.5, 1H), 8.11 (dd, J=2.3, 8.7, 1H), 7.64-7.58 (m, 1H), 7.33-7.23 (m, 4H), 7.06-6.96 (m, 4H), 4.17 (s, 2H), 3.60 (t, J=6.5, 2H), 2.83 (t, J=6.5, 2H); MS (ESI+) m/z 476.0 (M+H)+.
Reaction SMILES: CS[C:3]1[N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[CH:6]=[N:5][N:4]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:3]2[N:8]3[CH:9]=[CH:10][N:11]=[C:7]3[CH:6]=[N:5][N:4]=2)[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: CSc1nncc2nccn12
Product: CN1CCN(c2nncc3nccn23)CC1

Procedure:
A 5.0 gm. portion of 5-(methylthio)-imidazo[1,2-d]-as-triazine is combined with 45 ml. of N-methylpiperazine and refluxed for 5 hours. The reaction mixture is evaporated giving a brown oil. This oil is triturated four times with 30 ml. portions of hot benzene. The combined benzene solutions are treated with charcoal, evaporated to 75 ml., retreated with charcoal, cooled and filtered, giving 1.0 gm. of the desired product, m.p. 176°-178° C. This base forms non-toxic acid-addition salts with a variety of pharmacologically acceptable organic and inorganic salt-forming reagents. Thus, acid-addition salts, formed by admixture of the organic free base with an equivalent of an acid, suitably in a neutral solvent, are formed with such acids as sulfuric, phosphoric hydrochloric, sulfamic, citric, lactic, tartaric, acetic, benzoic, gluconic, ascorbic, and related acids. For purposes of this invention, 5-(4-methyl-1-piperazinyl)-imidazo[1,2-d]-as-triazine is equivalent to its non-toxic acid-addition salts.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:44])[N:10]([CH2:41][CH:42]=[CH2:43])[C:11]1[C:16](=[O:17])[N:15]2[C@H:18]([C:25]([N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[CH2:19][C@:20](N=[N+]=[N-])([CH3:21])[C:14]2=[N:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45]([O:49][C:50](=[O:86])[CH2:51][C@@]1(C)C2=NC=C(N(CC=C)C(OCC3C=CC=CC=3)=O)C(=O)N2[C@@H](C(=O)NC2C=CC=CC=2)C1)([CH3:48])([CH3:47])[CH3:46]>>[C:45]([O:49][C:50](=[O:86])[CH2:51][C@@:20]1([CH3:21])[C:14]2=[N:13][CH:12]=[C:11]([N:10]([CH2:41][CH:42]=[CH2:43])[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:44])[C:16](=[O:17])[N:15]2[C@@H:18]([C:25]([N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])[CH2:19]1)([CH3:48])([CH3:47])[CH3:46]
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)N(C(=O)OC(C)(C)C)c1ccccc1)C[C@@]2(C)N=[N+]=[N-]
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)Nc1ccccc1)C[C@@]2(C)CC(=O)OC(C)(C)C
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)N(C(=O)OC(C)(C)C)c1ccccc1)C[C@@]2(C)CC(=O)OC(C)(C)C
Yield: 82 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 18e, intermediate 38a (435.9 mg, 0.76 mmol), was protected to give 418.9 mg (82%) of intermediate 38b. MS (ESI) 673.4 (M+H+), 695.3 (M+Na+).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[F:21][C:22]1[CH:35]=[CH:34][C:25]([O:26][C:27]2[O:31][C:30]([C:32]#[CH:33])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1.[CH:36](=[O:38])[CH3:37]>C1COCC1>[F:21][C:22]1[CH:35]=[CH:34][C:25]([O:26][C:27]2[O:31][C:30]([C:32]#[C:33][CH:36]([OH:38])[CH3:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1
Reactant: CC=O
Reactant: C#Cc1ccc(Oc2ccc(F)cc2)o1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)C#Cc1ccc(Oc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
Lithium diisopropylamide was generated by the addition of n-butyl lithium (14.2 mL, 35,4 mmol, 2.5M in hexanes) to a stirred -78° C. THF (100 mL) solution as of diisopropylamine (3.58 g, 35.4 mmol) followed by warming to -5° C. (ice/methanol) and stirring for 0.5 hours. To this stirred solution was added the 2-[5-(4-fluorophenoxy)-2-furyl]-ethyne (6.5 g, 32.2 mmol) prepared in step 3 as a THF solution via syringe. The reaction was stirred 0.5 hours and acetaldehyde (3.11 g, 70.8 mmol) was added via syringe, the ice bath was removed, and the reaction warmed to room temperature. Water was added and most of the THF removed in vacuo. The resulting mixture was partitioned between water and ethyl acetate. The combined ethyl acetate layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (30% ether/hexanes) to give 6.39 g (73%) of 4-[5-(4-fluorophenoxy)-2-furyl]-3-butyne-2-ol as a slightly yellow solid. mp(ether/hexanes) 56°-57.5° C. 1H NMR (300 MHz, CDCl3) δ 1.54 (d, 3H, J=7 Hz), 1.88 (d, 1H, J=6 Hz), 4.75 (m, 1H), 5.47 (d, 1H, J=4 Hz), 6.53 (d, 1H, J=4 Hz), 7.04 (m, 4H). MS (DCI/NH3) m/e 247 (M+H)+, 229.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:5]2.[Li]CCCC.[C:26](=[O:28])=[O:27]>C1COCC1>[Si:14]([O:13][CH2:12][C:6]1[N:7]([CH3:11])[C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([C:26]([OH:28])=[O:27])=[CH:10][CH:9]=2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: O=C=O
Reactant: Cn1c(CO[Si](C)(C)C(C)(C)C)cc2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(CO[Si](C)(C)C(C)(C)C)cc2cc(C(=O)O)ccc21

Procedure:
To a stirred solution of 5-bromo-2-((tert-butyldimethylsilyloxy)methyl)-1-methyl-1H-indole (5.32 g, 15.0 mmol), prepared according to procedure described in Example 39, Step 3, in THF (30 mL) was added n-BuLi (2.5 M solution in hexanes, 7.30 mL, 18.25 mmol, 1.2 eq) at −78° C. dropwise. The mixture was stirred for 30 min at −78° C. before dry CO2 (g) was bubbled into reaction for 10 min. The reaction was quenched with saturated aqueous NH4Cl then extracted by CH2Cl2 (3×50 mL). The combined organic layers were dried over Na2SO4 then concentrated under reduced pressure to give the title compound (4.80 g, ca. 15.0 mmol) in quantitative yield. The acid was carried over to next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH3:11])[C:6]([O:12][CH3:13])=[C:5]([CH3:14])[C:4]=1/[CH:15]=[C:16](\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)/[C:17]([O:19]CC)=[O:18].[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH3:11])[C:6]([O:12][CH3:13])=[C:5]([CH3:14])[C:4]=1/[CH:15]=[C:16](\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)/[C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)/C(=C/c1c(C)c(OC)c(OC)c(C)c1OC)CCCCCc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C)c(OC)c(OC)c(C)c1/C=C(\CCCCCc1cccnc1)C(=O)O
Temperature: 0 °C
Yield: 98.6 %

Procedure:
177 g (0.39 mol) of the ester prepared in Example 1 was dissolved in 500 ml of ethanol, followed by the addition of 100 ml of an aqueous solution of 78 g of sodium hydroxide. The obtained mixture was heated under reflux for one hour, followed by the addition of 1 l of ice. The obtained mixture was neutralized with 6N hydrochloric acid. The resulting mixture was extracted with 1 l of ethyl acetate twice. The organic layer was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and distilled to remove the solvent. 159 g of the title compound was obtained as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH2:10][CH:9]([C:12]([CH3:14])=[O:13])[O:8][CH2:7][C:6]=2[C:5](=[O:15])[CH:4]=[CH:3]1.C(O[CH:20]=[CH:21][CH:22]=[CH2:23])(=O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>C1C=CC=CC=1>[O:1]=[C:2]1[C:11]2[CH2:10][CH:9]([C:12]([CH3:14])=[O:13])[O:8][CH2:7][C:6]=2[C:5](=[O:15])[C:4]2[C:3]1=[CH:20][CH:21]=[CH:22][CH:23]=2
Reactant: CC(=O)C1CC2=C(CO1)C(=O)C=CC2=O
Reactant: C=CC=COC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)C1CC2=C(CO1)C(=O)c1ccccc1C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
A mixture of methyl (5,8-dioxo-3,4,5,8-tetrahydrobenzo[2,3-C] pyran-3-yl) ketone (100 mg, 0.485 mmol) and acetoxybutadiene (75 μl, 0.630 mmol) in dry benzene (5 mL) was heated for 12 hours at 60° C. under argon atmosphere. The solvent was then removed in vacuo and the resulting adduct dried under reduced pressure. The adduct was dissolved in 10 mL of ethanol and to this solution was added 1 mL of 1% K2CO3 aqueous solution. After stirring for 2 hours at R.T., the reaction mixture was neutralized (pH=6) and extracted with CH2Cl2 (2×50 mL). The organic layer was then washed with water (3×50 mL) and dried over MgSO4. Flash chromatography (toluene:ethyl acetate; 95%:5%) of the residue gave 69 mg (55% yield) of pure titled compound. (MP: 135°-136° C.).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[CH3:28]>>[F:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[C:20]([CH3:28])[CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1cc(-c2cc(F)cc3c(C)c4n(c23)CCNC4=O)ccc1F

Procedure:
The title compound, light yellow solid (69 mg, 85%), MS (ISP) m/z=327.5 [(M+H)+], mp 236° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: [CH:1]1([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc2nc(C3CCCC3)ccc2c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1ccc2c(c1)CCC(C1CCCC1)N2
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a solution of 2-cyclopentylquinoline (7.95 g, 40.3 mmol) and nickel (II) chloride hexahydrate (1.63 g, 6.85 mmol) in methanol (120 ml) cooled in an ice/methanol bath was added sodium borohydride (6.1 g, 161.2 mmol) portionwise over 1.5 h. The cooling bath was removed and the reaction stirred for a further 30 minutes. The methanol was then removed in vacuo. To the resulting black precipitate was added 2 M hydrochloric acid (100 ml) and then basified with 10 M potassium hydroxide. The mixture was poured into a separating funnel and extracted with ether (4×200 ml). The combined organic layers were dried (MgSO4), filtered and the solvent removed in vacuo to give 2-cyclopentyl-1,2,3,4-tetrahydroquinoline (7.45 g, 37.1 mmol) as a light brown oil.
Reaction SMILES: C([O-])(=O)C(C1C=CC=CC=1)O.[CH3:12][N:13]([CH3:23])[CH2:14][CH2:15][C@@H:16]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[OH:17].O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:23][N:13]([CH3:12])[CH2:14][CH2:15][CH:16]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[OH:17]
Reactant: CN(C)CC[C@H](O)c1cccs1
Agent: O=C([O-])C(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN(C)CCC(O)c1cccs1
Temperature: 2.5 °C
Reaction time: 0.33 h

Procedure:
A mixture of 62 Kgs. of mandelate salt of (S)-3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol, 125 liters of water and 375 liters of methylene chloride is cooled to 0-5° C. Adjusted the pH of the reaction mixture to 9.8 with 10% sodium carbonate solution at 0-5° C. Stirred the reaction mixture for 20 minutes at 0-5° C. Separated the organic and aqueous layers. Extracted the aqueous layer with methylene chloride. Washed the organic layer twice with 10% sodium chloride solution. Distilled the solvent completely under reduced pressure at below 35° C. Added 19 liters of cyclohexane to the above reaction mixture. Distilled the solvent completely under reduced pressure at below 35° C. Added 125 liters of cyclohexane to the above reaction mixture. Heated the reaction mixture to 40-45° C. and stirred for 60 minutes. Cooled the reaction mixture to 0-5° C. Filtered the precipitated solid and washed with cyclohexane. Dried the material at 40-45° C. for 6 hours to get the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[C:22]([CH3:33])[CH:21]=1)=[O:4].[CH3:34][NH:35][CH3:36].C1COCC1>CO>[CH3:34][N:35]([CH3:36])[CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[C:22]([CH3:33])[CH:21]=1)=[O:4]
Reactant: Cc1cc(Nc2ncnc3ccc(C#CCNC(=O)CCl)cc23)ccc1Oc1cccnc1
Reactant: CNC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncnc3ccc(C#CCNC(=O)CN(C)C)cc23)ccc1Oc1cccnc1
Yield: 99 %

Procedure:
To a solution of 2-Chloro-N-(3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide (99 mg, 0.20 mmol) in MeOH (5 mL) was added a solution dimethylamine in THF (2 mL, 4.0 mmol). The resulting solution was refluxed under nitrogen for 1 hour. After concentration, the residue was further dried, dissolved in MeOH (1.0 mL), and treated with HCl gas for 3 minutes. The resulting solution was added to EtOAc with vigorous stirring to precipitate the HCl salt product as yellow solid which was collected by vacuum-filtration, rinsed with EtOAc, and further dried to give 110 mg (99%) of the title compound. 1H NMR (CD3OD) δ 2.30 (s, 3H), 2.96 (s, 6H), 4.03 (s, 2H), 4.37 (s, 2H), 7.27 (d, 1H), 7.72 (dt, 1H), 7.81(m, 1H), 7.84 (d, 1H), 8.03 (dd, 1H), 8.06 (d, 1H), 8.13 (dd, 1H), 8.59 (d, 1H), 8.68 (s, 1H), 8.81 (s, 1H), 8.84 (s, 1H); MS m/z (MH+) 467.3.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[C:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])[CH3:34]>>[C:33]([N:36]1[CH2:41][CH2:40][N:39]([C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:6]3[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]4[S:12][CH:13]=[C:14]([C:16]5[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=5)[N:15]=4)=[CH:8][CH:7]=3)=[CH:29][CH:28]=2)=[O:32])[CH2:38][CH2:37]1)(=[O:35])[CH3:34]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(C(=O)c2ccc(-c3ccc(-c4nc(-c5ccc(Cl)c(Cl)c5)cs4)cc3C(=O)O)cc2)CC1
Yield: 66.4 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 1-acetylpiperazine (available from Aldrich Chemical Company, Inc.; 79 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4′-(4-acetyl-piperazine-1-carbonyl)-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (81 mg, 68%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.24 (br s, 1H), 8.48 (s, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 2.0 Hz, 1H), 8.10 (dd, J=8.3, 2.0 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.45-7.53 (m, 4H), 3.46-3.59 (br s, 6H), 3.32-3.36 (s, 6H), 2.03 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[S:10](=O)[C:11]3[CH:16]=[N:15][CH:14]=[N:13][C:12]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C([Cl:21])=O>CN(C=O)C.ClCCCl>[Cl:21][C:16]1[C:11]2[S:10][C:9]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=3[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=[N+]([O-])c1cccc2c1S(=O)c1cncnc1-2
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1sc1c(Cl)ncnc12
Temperature: 85 °C

Procedure:
Dry DMF (5 drops) was added to a mixture of 6-nitrobenzothieno[3,2-d]pyrimidone (161 mg, 0.65 mmol) and oxalyl chloride (0.28 mL, 3.2 mmol) in 1,2-dichloroethane (5 mL). The reaction was heated at 85° C. for 7.5 hours then cooled to 25° C. The solid was Buchner filtered and washed with CH2Cl2 and air dried. 4-Chloro-6-nitrobenzothieno[3,2-d]pyrimidine was obtained as a gray solid (166 mg, 96% crude).
Reaction SMILES: [F:1][C:2]1([F:15])[O:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][CH2:12][C:13]#[CH:14])=[CH:10][C:4]=2[O:3]1.[C:16]([N:19]=[C:20]=[S:21])(=[O:18])[CH3:17]>C1COCC1>[F:15][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:12][C:13](=[CH2:14])[S:21]/[C:20]/3=[N:19]\[C:16](=[O:18])[CH3:17])=[CH:10][C:4]=2[O:3]1
Reactant: C#CCNc1ccc2c(c1)OC(F)(F)O2
Reactant: CC(=O)N=C=S
Solvent: C1CCOC1
Product: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)/C(=N/C(C)=O)S1

Procedure:
A solution of Example 1 (1.4 g, 6.63 mmol) and acetyl isothiocyanate (0.60 mL, 6.63 mmol) in dry THF (25 mL) was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue purified by column chromatography using DCM as eluant to provide the titled compound. 1H NMR (CDCl3) δ ppm 2.20 (3H), 3.73 (2H), 4.85-5.00 (2H), 7.00-7.25 (3H); MS (ESI) 313 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[F:20])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[NH:27][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[F:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cc(F)ccc1F
Reactant: NC1CCCCC1
Product: CC(C)(C)OC(=O)NC(C(=O)NC1CCCCC1)c1cc(F)ccc1F
Yield: 89.9 %

Procedure:
Using general procedure E, tert-butoxycarbonylamino-(2,5-difluorophenyl)-acetic acid (1.84 g, 6.40 mmol) and cyclohexylamine (730 μL, 634 mg, 6.40 mmol) afforded [cyclohexylcarbamoyl-(2,5-difluorophenyl)-methyl]-carbamic acid tert-butyl ester (2.12 g, 90%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[CH3:15][NH:16][C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20]>>[CH3:15][NH:16]/[C:17](/[NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=1)=[CH:18]\[N+:19]([O-:21])=[O:20]
Reactant: CNC(=C[N+](=O)[O-])SC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Product: CN/C(=C\[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Yield: 90.6 %

Procedure:
The process of Example 1 was repeated at a commercial scale, using 2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (35 kg) and N-methyl-1-(methylthio)-2-nitroetheneamine (28 kg) to give crude ranitidine base (46.5 kg), m.p. 68°-70° C.; purity--99.1% (HPLC).
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+].I[CH2:38][CH:39]([CH3:41])[CH3:40]>C(#N)C>[CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:4]1=[O:24])[CH3:2]
Reactant: CC(C)CI
Reactant: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC#N
Product: CC[C@@H]1C(=O)N(CC(C)C)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Temperature: 74 °C
Reaction time: 12 h
Yield: 34.2 %

Procedure:
To a stirred solution of (3R)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 8) (0.25 g, 0.76 mmol) in acetonitrile (6 mL) under nitrogen was added cesium carbonate (0.13 g, 0.40 mmol), potassium carbonate (0.055 g, 0.40 mmol) and 1-iodo-2-methylpropane (0.30 mL, 0.48 g, 2.6 mmol). The mixture was stirred at 74° C. for 12 h. The solvent was then evaporated, and the residue was partitioned between methylene chloride and water. The organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated in vacuo. The product was purified via Biotage Horizon® (SiO2, gradient from 4% EtOAc/hexane to 38% EtOAc/hexane) to yield 0.10 g (35%) of (3R)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-1-isobutyl-3,4-dihydroquinoxalin-2(1H)-one.