Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.[C:16]([O:20][CH3:21])(=[O:19])[NH:17][NH2:18]>CO>[CH3:21][O:20][C:16](=[O:19])[NH:17][N:18]=[C:1]([CH:2]([CH3:4])[CH3:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)C(=O)c1ccccc1
Reactant: COC(=O)NN
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)NN=C(c1ccccc1)C(C)C

Procedure:
To a solution of 44.46 g (0.3 moles) of isobutyrophenone in 200 ml of methanol 3 ml of acetic acid and 27 g of methyl carbazate are added. The reaction mixture is boiled in a flask equipped with a reflux condenser, then clarified and evaporated in vacuo to half of its original volume. The residue is cooled and the separated tallow-like product is filtered off. Yield: 64.2 g (97.3%) M.p.: 78°-80° C. The product can be recrystallized from petrol.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[CH3:9][O:10][N:11]=[CH:12][C:13]1[CH:18]=[C:17]([NH2:19])[C:16]([F:20])=[CH:15][C:14]=1[Cl:21]>C1(C)C=CC=CC=1>[CH3:9][O:10][N:11]=[CH:12][C:13]1[CH:18]=[C:17]([N:19]=[C:2]=[O:1])[C:16]([F:20])=[CH:15][C:14]=1[Cl:21]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CON=Cc1cc(N)c(F)cc1Cl
Solvent: Cc1ccccc1
Product: CON=Cc1cc(N=C=O)c(F)cc1Cl
Temperature: 110 °C

Procedure:
411.3 g of diphosgene (2.08 mol) were added dropwise to a solution of 383 g (1.89 mol) of 5-amino-2-chloro-4-fluorobenzaldehyde (O-methyl)oxime in 2 l of toluene. The temperature was then slowly raised to 110° C. in the course of approximately 6 hours so that the evolution of gas proceeded in a controlled manner. The mixture was subsequently refluxed for a further 5 hours. The reaction mixture was then left to cool and finally concentrated. Yield: 432 g.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N:33][N:34]=2)[N:31]=1>CN(C)C=O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([C:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N:33][N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Temperature: 70 °C
Yield: 26.1 %

Procedure:
5.15 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 3.6 g of ethyl 6-chloro[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate were dissolved in 70 ml of N,N-dimethylformamide; 5.48 ml of N-ethyldiisdpropylamine was added, followed by stirring under heating at an external temperature of 70° C. for 4 hours. After cooling, cold saline was added; the reaction mixture was extracted with tetrahydrofuran and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; half of the precipitated crystal was recrystallized from ethanol-ethyl acetate (1:1), collected by filtration, and dried, to yield 2.13 g of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]1[CH2:11][CH:10]([C:12]2[N:16]3[CH:17]=[CH:18][N:19]=[C:20]([CH3:21])[C:15]3=[C:14]([Br:22])[N:13]=2)[CH2:9]1.C([BH3-])#N.[Na+].[OH-].[Na+]>ClCCl.C(O)(=O)C>[Br:22][C:14]1[N:13]=[C:12]([CH:10]2[CH2:9][N:8]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH2:11]2)[N:16]2[CH:17]=[CH:18][N:19]=[C:20]([CH3:21])[C:15]=12
Reactant: O=C1CCOCC1
Reactant: Cc1nccn2c(C3CNC3)nc(Br)c12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nccn2c(C3CN(C4CCOCC4)C3)nc(Br)c12
Yield: 5.8 %

Procedure:
To tetrahydro-4-h-pyran-4-one (3.74 mmol, 0.346 ml) in dichloromethane (5 ml) and acetic acid (0.306 ml) was added 3-(azetidin-3-yl)-1-bromo-8-methylimidazo[1,5-a]pyrazine (1.872 mmol, 500 mg) in dichloromethane (10 ml) and after stirring for 20 minutes under a nitrogen atmosphere at room temperature sodium cyanoborohydride (3.74 mmol, 235 mg) was added in portions. After one hour the reaction mixture was quenched with water, a saturated aqueous sodium hydrogencarbonate solution was added (pH of reaction mixture ˜7) followed by 2M sodium hydroxide until the pH reached 11 and extracted three times with dichloromethane. The organic layers were combined, filtered through a phase separation filter and concentrated in vacuo. Purification by column chromatography (silica gel; dichloromethane with gradient 0 to 10% methanol) gave 1-bromo-8-methyl-3-(1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl)imidazo[1,5-a]pyrazine (38 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])(CC)C.C1CCCCC1.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1>O1CCCC1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:25]2([OH:28])[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CN1CCC(=O)CC1
Reactant: COc1cccc(Br)c1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COc1cccc(C2(O)CCN(C)CC2)c1
Temperature: -50 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A suitable dry reaction vessel having a mechanical stirrer, low temperature thermometer and addition funnel was charged with 250 g (1.34 mol) of m-bromoanisole (Aldrich Chemical Company, Milwaukee, Wis.) in 675 ml of dry tetrahydrofuran and the solution was cooled under nitrogen to -50° C. to -55° C. in a dry ice/acetone bath. A solution of 1357 ml. of sec.-butyllithium in cyclohexane (1.71 mol) was added dropwise to the reaction mixture at such a rate so that the temperature did not rise above -50° C. The resulting white suspension was stirred at -50° C. for 1 hour followed by the addition of 174.2 g (1.54 mol) of 1-methyl-4-piperidone (Aldrich Chemical Company) in 440 ml of dry tetrahydrofuran so as to maintain the reaction temperature below -40° C. When the addition was complete the temperature was allowed to rise to approximately -20° C. over approximately 11/2 hours and then to room temperature over a 1 hour period. Residual sec.-butyllithium was quenched by the addition of 350 ml of saturated sodium chloride solution followed by the addition of 525 ml of water. The aqueous phase was separated and extracted twice with 350 ml portions of methylene chloride. The combined organic extracts were extracted in two portions, each with 1250 ml of 1N hydrochloric acid. The separated aqueous extracts were made basic (pH=10) with 28 percent ammonium hydroxide and extracted 3 times with 350 ml portions of methylene chloride. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue was slurried in 1000 ml of hot hexane and the slurry was cooled and filtered. The isolated crystalline product was dried in a vacuum oven to provide 225.6 g of 98% pure product.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([CH3:14])[C:5](=[O:13])[N:6]([CH2:9][CH:10]([OH:12])[CH3:11])[C:7]=1[NH2:8].C(Cl)(Cl)Cl.[CH3:20][CH2:21]OCC>C(O)(=O)C>[CH3:14][N:4]1[C:3](=[O:15])[C:2]2[NH:1][C:20]([CH3:21])=[N:8][C:7]=2[N:6]([CH2:9][CH:10]([OH:12])[CH3:11])[C:5]1=[O:13]
Reactant: CC(O)Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: CCOCC
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1nc2c([nH]1)c(=O)n(C)c(=O)n2CC(C)O

Procedure:
16 g (0.075 mol) of 5,6-diamino-1-(2-hydroxypropyl)-3-methyl-2,4-(1H, 3H)-pyrimidinedione (VI) was refluxed in 35 ml of acetic acid for 15 minutes. To the warm solution 30 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 16 g (VII). These crystals were refluxed in 40 ml of 2 N NaOH for 30 minutes and then neutralized with 18 ml of 5 N hydrochloric acid. Crystals were filtered off and recrystallized from 50 ml of water. Yield 6.6 g (VIII). NMR.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[CH:4][CH:3]=1.[OH:19][S:20](O)(=[O:22])=[O:21].O=S(=O)=O.N1C=CC=CC=1>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[CH:4][C:3]=1[S:20]([OH:22])(=[O:21])=[O:19]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Agent: O=S(=O)=O
Solvent: O
Solvent: c1ccncc1
Product: Nc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Temperature: 120 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
60 parts of 1,4-diaminoanthraquinone are added to 228 parts of 25% oleum over one hour and then 20 parts of pyridine are added. The temperature of the reaction mixture is 70°-80° C. and is further raised to 120° C. The reaction mixture is stirred at this temperature for 3 hours, then cooled to 70°-80° C., and 220 parts of water are slowly added dropwise. The resultant thick suspension is filtered at room temperature and the filter cake is washed with 100 parts of 50% sulfuric acid and subsequently dispersed in water. The pH of the aqueous suspension is then adjusted to 7.5 with 35% sodium hydroxide solution, whereupon the 1,4-diaminoanthraquinone-2sulfonic acid goes into solution. The solution is then heated to 85°-90° C. and 40 parts of magnesium sulfate are added. Upon cooling the reaction solution, the 1,4-diaminoanthraquinone-2-sulfonic acid crystallises in the form of the magnesium salt, which is isolated by filtration, washed with a 5% solution of magnesium sulfate and dried, affording 72.4 parts of the magnesium salt of 1,4-diaminoanthraquinone-2-sulfonic acid, corresponding to a yield of 85%. According to chromatographic analysis, the product is homogeneous with a trace of starting material. The Rf value is 0.57, which confirms that this product is identical with that obtained in Example 1.
Reaction SMILES: [CH2:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1(=[C:17](CCCC)[CH:18]=[O:19])CCCC[CH2:12][CH2:11][CH2:10]1>>[C:1]1(=[CH:12][CH2:11][CH2:10][CH2:9][CH2:17][CH:18]=[O:19])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCCCCCC1
Reactant: CCCCC(C=O)=C1CCCCCCC1
Product: O=CCCCCC=C1CCCCCCC1

Procedure:
6-cyclooctylidenehexanal is prepared according to the protocol described in Example 7 using cyclooctane in place of 2,4,4-trimethylcyclopentanone. The crude product containing cyclooctylidenehexanal is distilled under reduced pressure: its boiling point is 94° C. at 0.2 torr.
Reaction SMILES: [CH3:1][N:2](C)/C=N/[H].[Br:7][C:8]1[CH:9]=[C:10]([CH3:17])[C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=1.CC([O-])(C)C.[K+].Cl>C1COCC1>[Br:7][C:8]1[CH:13]=[N:12][C:11]2[C:14](=[O:16])[NH:2][CH:1]=[CH:17][C:10]=2[CH:9]=1
Reactant: [H]/N=C/N(C)C
Reactant: Cc1cc(Br)cnc1C(=O)O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1[nH]ccc2cc(Br)cnc12
Temperature: 25 °C

Procedure:
5-Bromo-3-methyl-pyridine-2-carboxylic acid 1-dimethylamino-meth-(E)-ylideneamine (2.5 g, 9.25 mmol) was dissolved in THF (20 ml). KOtBu (1.565 g, 13.05 mmol) in THF (30 ml) was added dropwise and the reaction mixture was heated to reflux for 3 h and then cooled to rt. The pH was adjusted to 7 with concentrated HCl. The reaction mixture was concentrated. The brown solid obtained was triturated with water (10 ml). The solid thus obtained was collected by filtration (2 g, 8 mmol).
Reaction SMILES: O.[C:2](Cl)([Cl:4])=[O:3].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>C(Cl)Cl>[Cl:4][C:2]([O:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(Cl)Cl
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(Cl)Oc1ccccc1

Procedure:
Phenyl chloroform ate was prepared in a stirred reactor at a temperature which was kept below 10° C. by cooling. 1320 ml of methylene chloride were provided in the reactor together with 150 ml of water. 7.4 g/minute of phosgene were dosed for 10 minutes. 70.5 g of phenol in 333 ml of methylene chloride were then dosed in the course of 35 minutes. During this dosing of phenol, 3.7 g/min. of phosgene were added. The pH was kept at a value of 2-4 by dosing with sodium hydroxide solution. During the dosing of phenol 30 ml of water were added four times to the reactor. After termination of the phenol dosing, the phosgene dosing was continued for another 3 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]2[C:23]([C:24]3[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][CH:25]=3)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][N:20]=3)[N:15]=2)=[N:7][CH:8]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]2[C:23]([CH:24]3[CH2:25][CH2:26][CH2:27][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29]3)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][N:20]=3)[N:15]=2)=[N:7][CH:8]=1
Reactant: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2C2=CCCN(C(=O)OC(C)(C)C)C2)nc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2C2CCCN(C(=O)OC(C)(C)C)C2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 5-(2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-1,5-naphthyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (RR1) (50 mg, 0.10 mmol) in ethanol (2 mL) was carefully added 10% palladium on carbon (10.6 mg, 0.01 mmol) under N2. The reaction mixture was evacuated and backfilled three times with hydrogen via balloon and then stirred overnight at room temperature. Upon completion, the mixture was filtered through celite washing with methanol and concentrated in vacuo to afford the title compound. 1H NMR (500 MHz, DMSO): δ 8.77 (1 H, d, J=4.5 Hz), 8.12 (3 H, d, J=9.4 Hz), 7.64 (1 H, m), 7.24 (2 H, s), 4.53 (m, 2 H), 4.26 (m, 2 H), 3.77 (s, 3 H), 3.49-3.40 (m, 3 H), 2.27 (s, 2 H), 2.24-2.19 (m, 1 H), 1.99 (m, 1 H), 1.80 (s, 1 H), 1.41 (s, 9 H), 1.23-1.15 (m, 2 H), 1.08 (dt, J=8.7, 4.6 Hz, 1 H); HRMS m/z (M+H) 491.2654 found, 491.2653 required.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:27])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=1.[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)C.CCCCCC>[CH2:28]([NH:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:27])[CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:17][CH2:18]2)[CH:7]=[CH:8][CH:9]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cccc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1cccc(NCc2ccccc2)c1

Procedure:
The title compound is prepared from N-(3-amino-phenyl)-2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-acetamid dihydrochloride (Example 183) and benzaldehyde according to the method described in Example 177. Melting Point: 98-100° C. (diethylether-hexane)
Reaction SMILES: [CH2:1]([C:13]1[CH:14]=[C:15]([C:18]2[NH:19][C:20](=[O:44])[C:21]3[C:25]=2[C:24](=[O:26])[NH:23][C:22]=3[C:27]2[S:28][CH:29]=[C:30]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:31]=2)[S:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Br[CH2:46][CH:47]([CH2:50][CH2:51][CH2:52][CH3:53])[CH2:48][CH3:49].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:32]([C:30]1[CH:31]=[C:27]([C:22]2[N:23]([CH2:17][CH:13]([CH2:14][CH3:15])[CH2:1][CH2:2][CH2:3][CH3:4])[C:24](=[O:26])[C:25]3[C:21]=2[C:20](=[O:44])[N:19]([CH2:46][CH:47]([CH2:48][CH3:49])[CH2:50][CH2:51][CH2:52][CH3:53])[C:18]=3[C:15]2[S:16][CH:17]=[C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:14]=2)[S:28][CH:29]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCC(CC)CBr
Reactant: CCCCCCCCCCCCc1csc(C2=C3C(=O)NC(c4cc(CCCCCCCCCCCC)cs4)=C3C(=O)N2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCCCCCCCCCCc1csc(C2=C3C(=O)N(CC(CC)CCCC)C(c4cc(CCCCCCCCCCCC)cs4)=C3C(=O)N2CC(CC)CCCC)c1
Temperature: 60 °C
Yield: 21.3 %

Procedure:
A 100 mL flask was charged with 3,6-bis-(4-dodecyl-thiophen-2-yl)-2,5-dihydro-pyrrolo[3,4-c]pyrrole-1,4-dione 4 (1.91 g, 3.0 mmol), 3-bromomethyl-heptane (1.54 g, 8.0 mmol), Cs2CO3 (2.93 g, 9.0 mmol) and then purged with argon for 10 minutes before 100 mL of dimethylformamide (DMF) was added. The mixture was heated at 60° C. overnight and then cooled to room temperature. Dichloromethane (50 mL) was added. The organic layer was washed with water (50 mL for 3 times) and then dried over anhydrous Na2SO4. Black solids were obtained after removal of the solvent and precipitation from methanol. The product was purified by column with dichloromethane/hexane (v/v: 2/1) as the eluent and weighed 0.55 g (overall yield: 21.3% from 4-dodecyl-thiophene-2-carbonitrile 3) after being dried.
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[NH:6]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7]1>>[CH:1]1([CH2:4][N:6]2[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7]2)[CH2:3][CH2:2]1
Reactant: O=CC1CC1
Reactant: OCC1CCNC1
Product: OCC1CCN(CC2CC2)C1

Procedure:
In a manner similar to Preparation 8, react cyclopropanecarboxaldehyde with 3-pyrrolidinemethanol to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11]([Cl:17])=[N:12][CH:13]=[N:14][C:15]=1Cl)=[O:9].[NH:18]1[CH2:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>C(#N)C>[N:18]1([C:15]2[C:10]([C:8]([C:3]3[CH:4]=[N:5][N:6]([CH3:7])[C:2]=3[Br:1])=[O:9])=[C:11]([Cl:17])[N:12]=[CH:13][N:14]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: Cn1ncc(C(=O)c2c(Cl)ncnc2Cl)c1Br
Reactant: C1CNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)c2c(Cl)ncnc2N2CCC2)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(5-Bromo-1-methyl-1H-pyrazol-4-yl)(4,6-dichloropyrimidin-5-yl)methanone (C26) (1.14 g, 3.39 mmol) was combined with azetidine (98%, 0.212 mL, 3.08 mmol) and N,N-diisopropylethylamine (0.645 mL, 3.70 mmol) in acetonitrile (30 mL) at 0° C. The mixture was then allowed to warm to room temperature and stir for 18 hours. After removal of volatiles in vacuo, the residue was purificed via silica gel chromatography (Eluent: 100:1 ethyl acetate/methanol) to afford the product. Yield: 1.07 g, 3.00 mmol, 97%. LCMS m/z 356.2, 358.2, 360.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.25-2.36 (m, 2H), 3.94 (s, 3H), 3.96-4.09 (br m, 4H), 7.85 (br s, 1H), 8.37 (s, 1H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH:12]=[C:13]1[N:17]([CH2:18][CH2:19][CH2:20][S:21][CH3:22])[C:16]2[CH:23]=[CH:24][C:25]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:26][C:15]=2[S:14]1.O>O1CCOCC1>[NH:12]=[C:13]1[N:17]([CH2:18][CH2:19][CH2:20][S:21]([CH3:22])=[O:9])[C:16]2[CH:23]=[CH:24][C:25]([O:27][C:28]([F:31])([F:29])[F:30])=[CH:26][C:15]=2[S:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)CCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Reaction time: 72 h
Yield: 27.2 %

Procedure:
90% m-chloroperbenzoic acid (2.5 g) is added in the course of about 15 minutes, at a temperature close to 20° C., to 2-imino-3-(3-methylthiopropyl)-6-trifluoromethoxybenzothiazoline (4.2 g) in solution in a mixture (100 cc) of water and dioxane (40/60 by volume). The reaction mixture is stirred at the same temperature for 72 hours. After adding to distilled water (500 cc) and neutralising with 1N sodium hydroxide solution, the reaction mixture is extracted with dichloromethane. After drying over magnesium sulphate and concentrating to dryness under reduced pressure and then purifying by chromatography on a silica column using a mixture of ethyl acetate and methanol (80/20 by volume) as eluent, (RS)-2-imino-3-(3-methylsulphinylpropyl)-6-trifluoromethoxybenzothiazoline (1.2 g) melting at 114° C. is obtained.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[CH:9]1([N:12]([CH3:22])[S:13]([N:16]2[CH:20]=[CH:19][N+](C)=C2)(=[O:15])=[O:14])[CH2:11][CH2:10]1.[C@H:23]1([NH:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=C(N)C=3)[N:34]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>>[CH:9]1([N:12]([CH3:22])[S:13]([NH:16][C:20]2[CH:19]=[C:40]3[C:35](=[CH:36][CH:37]=2)[N:34]=[C:33]([NH:32][C@H:23]2[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24]2)[CH:42]=[CH:41]3)(=[O:14])=[O:15])[CH2:10][CH2:11]1
Reactant: CN(C1CC1)S(=O)(=O)n1cc[n+](C)c1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CN(C1CC1)S(=O)(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with step C of the general method described in example 76 from 3-(cyclopropyl-methyl-sulfamoyl)-1-methyl-3-H-imidazol-1-ium trifluoromethanesulfonate and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=409.7 (M+H+).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].Cl[C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=1)[C:11]#[N:12]>C1COCC1.C(OCC)(=O)C>[CH:4]([O:6][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[N:15]=1)[C:11]#[N:12])([CH3:5])[CH3:3]
Reactant: N#Cc1cc(Cl)nc(C(F)(F)F)c1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1cc(C#N)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
In a 250-ml capacity 3 neck flask (1.39 g) NaH suspended in 100 ml THF. At 0° C. IPA (4.36 g) in 20 ml THF added in this reaction flask. Allow it to stir at RT for 3 h. At 0° C. 2-chloro-6-trifluoromethylisonicotinonitrile (10 g) in 80 mL THF added in the flask in dropwise manner. Maintained 0° C. temperature for 30 min. Completion of reaction conformed by TLC. Reaction mixture was dumped in ice water. Extract compound in ethyl acetate. Organic layer was washed by water two times & dried over Na2SO4, filtered, and concentrated by rotary evaporation (40° C., 20 mmHg) to afford 8 g of yellow oil. The resulting crude compound forwarded for next step.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:25](I)[CH3:26]>CN(C)C=O>[CH2:25]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:26]
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Temperature: 0 °C
Yield: 98 %

Procedure:
To a slurry of sodium hydride (60% suspension in oil, 7.5 g) and dimethyl formamide (70 ml) was added a solution of the racemic ethyl 2-hydroxy-3-(4-benzyloxyphenyl)propionate of the formula (10) (40 g) obtained according to the procedure described in step (iv) above in dimethylformamide (105 ml) at 5–10° C. over a period of 15–30 minutes. The temperature was allowed to attain room temperature and maintained at the same temperature for 1–3 h Ethyl iodide (36 g) was added slowly by maintaining the temperature at 25–30° C. over a period of 2–3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was dumped into ice water and extracted with toluene. The combined organic extracts were washed with water and the solvent was removed under reduced pressure to afford the title compound of the formula (12a) (47–48 g, 98–99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12].[H][H]>[Pd].O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1cc(N)ccc1F

Procedure:
A suspension of 10 grams of 2-fluoro-5-nitroanisole and 100 ml. of dioxane is reduced catalytically under 40 p.s.i. of hydrogen and 1.0 gram of 5% Pd/C. After the uptake of hydrogen ceases, the catalyst is filtered, and the filtrate is concentrated in vacuo to yield 4-fluoro-3-methoxyaniline.