Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[C:15]2[CH:24]=[CH:23][NH:22][C:16]=2[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=1.CN1C=C(C2C=C([N+]([O-])=O)C=CC=2OC2C=CC=CC=2)C2C=CNC=2C1=O>>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=2[F:1])=[C:6]([C:14]2[C:15]3[CH:24]=[CH:23][NH:22][C:16]=3[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=2)[CH:7]=1
Reactant: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccc(F)cc2F)c2cc[nH]c2c1=O
Agent: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Product: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)cc2F)c2cc[nH]c2c1=O

Procedure:
Example 27b was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 27a for the product of Example 2b, to provide the title compound.
Reaction SMILES: [OH-].[Na+:2].[O:3]=[S:4]1(=[O:36])[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[C:31]([NH:33][CH3:34])=[O:32])=[O:21])[C:17]([OH:35])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2.CC(C)=O.C(#N)C>O>[O:36]=[S:4]1(=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[C:31]([NH:33][CH3:34])=[O:32])=[O:21])[C:17]([O-:35])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2.[Na+:2]
Reactant: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CC#N
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydroxide (150 μL, 0.15 mmol, 1N solution) was added to a cloudy solution of 5-(1,1-dioxido-1,2-thiazinan-2-yl)-N-{4-fluoro-2-[(methylamino)carbonyl]benzyl}-8-hydroxy-1,6-naphthyridine-7-carboxamide (73 mg, 0.15 mmol) in a 2 mL mixture of acetone, acetonitrile and water. The homogeneous bright yellow solution was allowed to stir at room temperature for 30 minutes. The solvent was removed in vacuo and dried overnight on the high vac with gentle heating to give the desired product as a bright yellow solid.
Reaction SMILES: [CH:1]1([NH:6][C@@H:7]([CH2:12][CH3:13])[C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[Cl:19][C:20]1[N:25]=[C:24](Cl)[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1.ClCCl>C1CCCCC1>[Cl:19][C:20]1[N:25]=[C:24]([N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C@@H:7]([CH2:12][CH3:13])[C:8]([O:10][CH3:11])=[O:9])[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CC[C@H](NC1CCCC1)C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC[C@@H](C(=O)OC)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 85 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
Methyl (2S)-2-(cyclopentylamino)butanoate 41c (17.36 g, 93.69 mmol) was dissolved in 180 mL of cyclohexane followed by the addition of sodium bicarbonate (31.48 g, 0.37 mol) and 2,4-dichloro-5-nitro-pyrimidine (21.81 g, 0.11 mol) successively. The reaction solution was heated to 85° C. and stirred for 2 hours. The resulting solution was cooled down to room temperature, added with 300 mL of dichloromethane, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system B to obtain the title compound methyl (2S)-2-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]butanoate 41d (14.24 g, yield: 44.3%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:20][CH:21]([CH3:24])[CH2:22][Cl:23]>CN(C)C=O>[Cl:23][CH2:22][CH:21]([CH3:24])[CH2:20][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Reactant: CC(CCl)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CCl)CC(C#N)(C#N)Cc1ccc(C(F)(F)F)cc1
Yield: 61.5 %

Procedure:
Using 0.22 g of 2-(4-(trifluoromethyl)benzyl)malononitrile, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.33 g of 1-bromo-3-chloro-2-methylpropane, and according to the process described in the Production Example 1, there was obtained 0.19 g of 2-(3-chloro-2-methylpropyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (86)).
Reaction SMILES: CC1(C)CC=C(C2SC=CN=2)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC1=2.[CH3:29][C:30]1([CH3:59])[CH2:39][CH:38]=[C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:36]2[CH:35]=[C:34]([C:46]#[C:47][C:48]3[CH:58]=[CH:57][C:51]([C:52]([O:54]CC)=[O:53])=[CH:50][CH:49]=3)[CH:33]=[CH:32][C:31]1=2>>[CH3:29][C:30]1([CH3:59])[CH2:39][CH:38]=[C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:36]2[CH:35]=[C:34]([C:46]#[C:47][C:48]3[CH:49]=[CH:50][C:51]([C:52]([OH:54])=[O:53])=[CH:57][CH:58]=3)[CH:33]=[CH:32][C:31]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccc2)=CCC3(C)C)cc1
Agent: CC1(C)CC=C(c2nccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Product: CC1(C)CC=C(c2ccccc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(5,6-dihydro-5,5-dimethyl-8-(2-thiazolyl)-2-naphthalenyl)ethynyl]benzoic acid (Compound 30a), 27.0 mg (0.07 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthalenyl)ethynyl]benzoate (Compound 1a) was converted into the title compound (colorless solid) using 5.9 mg (0.14 mmol) of LiOH in H2O. PMR (d6 -DMSO): δ 1.31 (6H, s), 2.35 (2H, d, J=4.5 Hz), 6.05 (1H, t, J=J=J=4.5 Hz), 7.00 (1H, s), 7.33 (2H, d, J=6.2 Hz), 7.44 (4H, m), 7.59 (2H, d, J=8.1 Hz), 7.90 (2H, d, J=8.1 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:27]4[C:23]([S:24][C:25]([C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=5)=[N:26]4)=[N:22][CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:38]>O1CCOCC1>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([C:25]2[S:24][C:23]3=[N:22][CH:21]=[C:20]([C:17]4[CH:18]=[N:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[N:15][CH:16]=4)[N:27]3[N:26]=2)[CH:33]=[CH:32][C:31]=1[O:34][CH3:35].[ClH:38]
Reactant: COc1ccc(-c2nn3c(-c4cnc(N5CCN(C(=O)OC(C)(C)C)CC5)nc4)cnc3s2)cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2nn3c(-c4cnc(N5CCNCC5)nc4)cnc3s2)cc1OC
Reaction time: 8 h

Procedure:
To a suspension of 4-{5-[2-(3,4-Dimethoxy-phenyl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-pyrimidin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (0.105 g, 0.201 mmol, 1 eq) in dioxane (1.5 mL) was added 4M HCl in dioxane (0.5 mL, 0.2 mmol, 10 eq) at 0° C. The reaction was allowed to warm to it and it was stirred overnight. After 18 h additional HCl (0.5 mL) was added and the reaction was stirred for 7 h. Solvents were removed under reduced pressure and the residue was treated with CH3CN. Solids were filtered off and washed with CH3CN to give the desired product as HCl salt (72 mg, 77%). HPLC-MS: (5-40% B in 8 min, 0.8 mL/min, 50° C.): tR=4.68 min, [M+H]+ m/z 424.2; 1H NMR (300 MHz, DMSO) δ 8.97 (s, 2H), 7.69 (s, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.49 (s, 1H), 7.16 (d, J=8.5 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.75 (m, 4H), 2.79 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[H][H]>[C].[Pd].C(O)(=O)C>[NH2:12][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(O)c2ncccc12
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(O)c2ncccc12

Procedure:
5-Amino-8-hydroxyquinoline was prepared by the reduction of 8-hydroxy-5-nitroquinoline (from Aldrich Chemical Co., Inc., Milwaukee, Wis.). Twenty-five grams (0.131 moles) of 8-hydroxy-5-nitroquinoline were placed in a 500 milliliter (ml) Parr bottle followed by 250 ml of glacial acetic acid and 1 g of 10% palladium carbon. The bottle was further filled with 3×105Pascals (Pa) (3 atmospheres) of hydrogen. The filled bottle was attached to the Parr shaker-type hydrogenation apparatus (from Parr Instrument Co., Moline, Ill.) and the bottle and its contents were shaken until theoretical uptake was complete (approximately 5-6 hours). Reduction of the nitro group to the amine group was verified by the theoretical uptake of hydrogen. The original pressure in the Parr reactor was 0.61 MPa (88 psi). A drop of 0.24 MPa (34.7 psi) indicated that the theoretical uptake of hydrogen had occurred. The reaction contents were filtered, and the liquors were concentrated to a black-purple tar using a rotoevaporator. To remove excess acetic acid from the 5-amino-8-hydroxyquinoline, the tar was spread onto the bottom of an aluminum pan. The pan and its contents were heated in a vacuum oven for about 16 hours until the contents (5-amino-8-hydroxyquinoline) were dry.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[CH3:19])[NH2:15].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[F:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: Cc1ccc(N)cc1F
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1F
Temperature: 140 °C
Reaction time: 0.67 h

Procedure:
A mixture of 2-chloro-3-nitropyridine (4.76 g, 30.0 mmol), 3-fluoro-4-methylaniline (3.75 g, 30.0 mmol) and potassium carbonate (8.29 g, 60.0 mmol) in dimethyl sulfoxide (30 mL) was stirred at 140° C. for 40 minutes. The reaction mixture was then cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as a black solid. Yield: 6.78 g, 27.4 mmol, 91%. 1H NMR (400 MHz, CDCl3) δ 10.11 (br s, 1H), 8.54 (dd, J=8.3, 1.8 Hz, 1H), 8.51 (dd, J=4.6, 1.8 Hz, 1H), 7.59-7.64 (m, 1H), 7.15-7.21 (m, 2H), 6.86 (dd, J=8.4, 4.6 Hz, 1H), 2.28 (d, J=2.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28](O)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])=[O:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([N:38]5[CH2:39][CH2:40][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]5)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(C(=O)c2ccc3c(n2)CCC2C3=NN(c3ccc(C#N)c(Cl)c3)C2C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
In a dried reaction flask, 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.421 g, 1.0 mmol), 1-methylsulfonylpiperazine (0.214 g, 1.303 mmol), DIEA (0.2 mL, 1.15 mmol), and HATU (0.418 g, 1.1 mmol) were added to a mixed solvent of DMF (4 mL) and dichloromethane (8 mL). The mixture was stirred at room temperature for 2 hr and was concentrated under reduced pressure. Water was added to the residue. The mixture was filtered to produce a crude yellowish-green solid, which was washed with methanol to produce a purified product (0.325 g) in 57.3% yield.
Reaction SMILES: [OH:1][C@H:2]([CH3:47])[C@H:3]([NH:16][C:17]([C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]([O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])[CH:27]=[C:26]([O:41][C@@H:42]([CH3:46])[CH2:43][O:44][CH3:45])[CH:25]=2)=[CH:22][CH:23]=1)=O)[CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].CS(O)(=O)=O.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:45][O:44][CH2:43][C@@H:42]([O:41][C:26]1[CH:25]=[C:24]([C:21]2[NH:20][C:19]([C:17]3[O:1][C@@H:2]([CH3:47])[C@@H:3]([CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:7]([CH3:9])[CH3:8])[CH:10]([CH3:11])[CH3:12])[N:16]=3)=[CH:23][CH:22]=2)[CH:29]=[C:28]([O:30][Si:31]([CH:32]([CH3:34])[CH3:33])([CH:35]([CH3:36])[CH3:37])[CH:38]([CH3:40])[CH3:39])[CH:27]=1)[CH3:46]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=N[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)[C@H](C)O3)[nH]2)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
N-{(2R,3R)-3-Hydroxy-1-[(tripropan-2-ylsilyl)oxy]butan-2-yl}-5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrole-2-carboxamide (2.52 g, 3.65 mmol) synthesized in Example (110b) was dissolved in tetrahydrofuran (20 mL), and anhydrous methanesulfonic acid (1.05 g, 6.03 mmol) and triethylamine (2.00 mL, 14.35 mmol) were added, followed by stirring at 50° C. for 1 day under nitrogen atmosphere. To the reaction solution, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-30%) to afford the desired compound (2.30 g, yield 94%) as a pale yellow liquid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]([NH:10][C@@H:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]3[OH:17])[S:9][C:5]=2[CH:4]=1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[OH:17][C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([CH:2]=[O:1])[CH:19]=[CH:18][C:6]=2[N:7]=1
Reactant: OCc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of (1R,2R)-2-((6-(hydroxymethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol from Step 1 of this Example (445 mg, 1.6 mmol) in CH2Cl2 (40 mL) was added manganese(IV) oxide (696 mg, 8.0 mmol) at rt. The reaction suspension was heated under reflux overnight. After cooling to rt, the reaction mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give crude 2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazole-6-carbaldehyde as a brown oil (440 mg, 99%), which was used to next step without further purification. LCMS (ESI) m/z 277 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4](Br)[CH2:5][CH2:6][CH2:7][CH3:8].[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:10])[CH:4]([NH:16][C:15]1[CH:17]=[CH:18][C:12]([F:11])=[C:13]([CH3:19])[CH:14]=1)[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC(Br)C(=O)OC
Reactant: Cc1cc(N)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(Nc1ccc(F)c(C)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 88 h
Yield: 44.8 %

Procedure:
To a solution of 2-bromo-hexanoic acid methyl ester (0.500 g, 2.404 mmol) and 4-fluoro-3-methylaniline (0.301 g, 2.404 mmol) in 15 mL of DMF, was added K2CO3 (1.661 g, 12.020 mmol). After stirring at room temperature under N2 for 88 h, the reaction mixture was diluted with 60 mL of water and extracted with dichloromethane (60 mL×3). The organic extracts were combined dried over anhydrous Na2SO4 and the solvent removed under reduced pressure. Flash chromatography (silica gel) eluting with 0-20% ethyl acetate/hexanes afforded the title compound as brown oil (0.273 g, 45% yield). LC-MS: tR=9.9 min; m/z 254 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:19][C:15]1[CH:14]=[C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1c(Cl)n(-c2cccc(Cl)c2)c2ccccc12
Reactant: C1CNCCN1
Product: O=Cc1c(N2CCNCC2)n(-c2cccc(Cl)c2)c2ccccc12
Yield: 64 %

Procedure:
2-Chloro-1-(3-chlorophenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(3-chlorophenyl-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde (64% yield) as a cream solid. ESI/MS 340 (M+H); RT 2.66 min.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[K].[CH3:16]C(C)([O-])C.CI.CC(C)([O-])C.[K+]>CN(C)C=O.C1C=CC=CC=1>[CH3:16][C:6](=[C:2]1[CH2:3][CH2:4][CH2:5][NH:1]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CC(C)(C)[O-]
Reactant: O=C(C=C1CCCN1)c1ccccc1
Agent: [K+]
Agent: [K]
Solvent: CI
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(C(=O)c1ccccc1)=C1CCCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
17.0 g of α-(2-pyrrolidinylidene-acetophenone and 11.3 g of potassium-tert.-butoxide are dissolved in a mixture of 8 ml of dimethylformamide and 170 ml of benzene. A solution of 25 g of methyl iodide in 25 ml of benzene is added dropwise within 30 minutes. The reaction mixture heats up to 38°. It is stirred for 2 hours at room temperature; to the reaction mixture is then added a further 2.5 g of potassium tert.-butoxide and it is subsequently stirred for 15 hours at room temperature. The cloudy reaction mixture is filtered clear with the aid of diatomaceous earth; it is concentrated by evaporation and the evaporation residue is chromatographed on a silica-gel column with an ethyl acetate/hexane mixture (volume ratio 1:1). There is obtained 2-methyl-2-(2-pyrrolidinylidene)-acetophenone, m.p. 91°-92° (from cyclohexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[CH:6]=[CH:7][C:8]=1[C:9]1[S:13][CH:12]=[N:11][CH:10]=1.[CH2:15]([C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24](Cl)[N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:14][C:5]2[CH:6]=[CH:7][C:8]([C:9]3[S:13][CH:12]=[N:11][CH:10]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1cc(N)ccc1-c1cncs1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Product: COc1cc(Nc2nc(C)cc(Cc3ccccc3)n2)ccc1-c1cncs1

Procedure:
The title compound was prepared from 3-methoxy-4-thiazol-5-yl-phenylamine (118 mg, 0.57 mmol) and 4-benzyl-2-chloro-6-methyl-pyrimidine (125 mg, 0.57 mmol) in analogous manner to the procedure described in example 1e). Obtained as a colorless wax (70 mg, 32%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][C:10]1([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[O:11]1.[I-].[K+]>CN(C)C=O>[N:1]1([CH2:9][C:10]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[O:11]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc(C2(CBr)OC2c2ccc(Cl)cc2Cl)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(C2(Cn3ccnc3)OC2c2ccc(Cl)cc2Cl)cc1
Reaction time: 8 h
Yield: 81 %

Procedure:
6.2 g of imidazole and 1.3 g of sodium hydride (50% strength dispersion in mineral oil) were dispersed in 50 ml of N,N-dimethylformamide, and a solution of 12 g of 2-bromomethyl-2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-oxirane (isomer B) and 5 g of potassium iodide in 50 ml of N,N-dimethylformamide was added at room temperature (20° C.). After 8 hours, the reaction solution was poured onto water and the mixture was extracted with ethyl acetate. The organic phase was washed with water and dried over sodium sulfate, the solvent was evaporated off under reduced pressure and the residue was recrystallized from diisopropyl ether. 9.4 g (82.5%) of 2-(1H-imidazol-1-yl-methyl)-2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-oxirane (isomer B) of melting point 109° C. were obtained (compound 2).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1([C:20]#[N:21])[CH2:19][CH2:18]OC[CH2:15]1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(COC)OC>[NH:21]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:14]2([CH2:15][CH2:18][CH2:19]2)[CH2:20]1
Reactant: N#CC1(c2ccccc2F)CCOCC1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: COCCOC
Product: c1ccc2c(c1)NCC21CCC1
Yield: 10.2 %

Procedure:
Add LiAlH4 (266 mg, 7.01 mmol) to a solution of 4-(2-fluoro-phenyl)-tetrahydro-pyran-4-carbonitrile (488 mg, 2.72 mmol) in dimethoxyethane (30 mL). Stir the solution at reflux for 4d, then add aq. Satd Rochelle's salt solution (30 mL) and stir for an additional 1 h at RT. Extract the mixture with Et2O (3×30 mL). Combine the organic extracts and wash with brine (30 mL). Dry, filter and concentrate the organic solution then purify the crude material by flash chromatography, using a linear gradient of 100% hexanes to 30% EtOAc/hexanes, to give the title compound (44 mg, 10%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.31 (m, 1H), 7.03 (dt, 1H, J=1.4, 7.5), 6.79 (dt, 1H, J=0.9, 7.5), 6.64 (d, 1H, J=7.9), 2.36 (m, 2H), 2.21 (m, 2H), 2.02 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1([CH2:7]O)[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.O=S(Cl)Cl.[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[S:26].CN1CCOCC1>ClCCCl>[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]1[S:26][CH2:7][C:2]2([CH2:6][CH2:5][CH2:4][CH2:3]2)[NH:1]1
Reactant: NC1(CO)CCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: Cl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Temperature: 100 °C
Yield: 81.1 %

Procedure:
To a solution of 1-amino-1-(hydroxymethyl)cyclopentane (Method B1c; 20.7 g, 180 mmol) and HCl (4M in p-dioxane, 400 mL) was added SOCl2 (15.7 mL, 216 mmol) and the resulting solution was heated at 100° C. for 18 h. The reaction mixture was concentrated under reduced pressure, then treated with 2-methyl4-nitrophenyl isothiocyanate (31.4 g, 162 mmol) and 1,2-dichloroethane (400 ml), followed by N-methylmorpholine (49 mL, 449 mmol). The resulting mixture was heated at 70° C. for 18 h, cooled to room temp. and concentrated under reduced pressure. The residue was treated with hot EtOAc, filtered and concentrated under reduced pressure. The residue was recrystallized (MeOH) to yield 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane (38.3 g, 81%): TLC (25% EtOAc/hex) Rf0.27.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]2[NH:12]C(=O)O[C:8](=[O:9])[C:7]=12.[NH3:15]>CN(C=O)C.O>[NH2:12][C:6]1[C:5]([CH3:14])=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]([NH2:15])=[O:9]
Reactant: Cc1ccc(Cl)c2c(=O)oc(=O)[nH]c12
Reactant: N
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)c(C(N)=O)c1N

Procedure:
Using the procedure of Example A3, the reaction of 98.8 g (0.467 mol) of 6-chloro-3-methylisatoic anhydride in 330 ml of DMF with 42 ml (0.560 mol) of 25% strength aqueous ammonia solution in 140 ml of water and a further 110 ml of water gave 24 g (37% of theory) of the title compound as a yellowish powder of m.p. 149-152° C.