Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>ClCCl>[Si:14]([O:6][CH2:5][CH:4]([OH:7])[CH2:3][N:2]([CH3:8])[CH3:1])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CN(C)CC(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CN(C)CC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A dry dichloromethane (10 mL) solution of 3-(dimethylamino)-1,2-propanediol (98%, 1.00 g, 8.39 mmol, 1.0 equiv) and imidazole (0.57 g, 8.39 mmol, 1.0 equiv) was stirred at 0° C. under argon for 15 minutes. Solid tert-butyldimethylsilyl chloride (1.26 g, 8.39 mmol, 1.0 equiv) was added to the mixture and the resultant was stirred for 2 hours at 0° C. The mixture was then diluted with 20 mL of dichloromethane and poured into deionized water (15 mL). The organic layer was separated and the aqueous layer was extracted with two additional portions of dichloromethane (20 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to afford crude 1-(tert-butyldimethylsilyloxy)-3-(dimethylamino)propan-2-ol, a thick clear oil, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[N:17][CH:18]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:19][C:15]1[CH:16]=[N:17][CH:18]=[C:13]([C:12]([F:21])([F:11])[F:20])[CH:14]=1)[CH:5]=[O:6]
Reactant: Oc1cncc(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2cncc(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D30 starting from 3,4-difluorobenzaldehyde and 5-(trifluoromethyl)pyridin-3-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1F)[C:25]([OH:27])=[O:26])#[N:21]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][C:30]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=2[C:20]#[N:21])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: N#Cc1cc(C(=O)O)ccc1F
Reactant: CC(C)COc1ncc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)COc1ncc(Oc2ccc(C(=O)O)cc2C#N)cc1Cl
Temperature: 90 °C
Reaction time: 16 h
Yield: 118.7 %

Procedure:
5-Chloro-6-isobutoxypyridin-3-ol (Preparation 16, 0.124 g, 0.62 mmol) and potassium carbonate (0.28 g, 2.03 mmol) were suspended in DMSO (3.0 mL). Then 3-cyano-4-fluorobenzoic acid (0.0835 g, 0.51 mmol) was added portionwise. The reaction was then stirred at 90° C. under nitrogen for 16 hours, diluted in EtOAc (15 mL) and washed twice with an aqueous solution of HCl (2.0 M, 10 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase column chromatography (ISCO®, gradient of 5-95% acetonitrile in water, 13 g C18 column) to afford the title compound as an orange oil (0.21 g, 120%):
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:28][CH:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:30]>>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:28][CH:29]([CH3:30])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:15]([S:18]([CH:21]([CH3:22])[CH3:23])(=[O:19])=[O:20])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)C(C)C
Reactant: CC(N)C(C)(C)C
Product: CC(NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)C(C)C)C(C)(C)C
Yield: 80 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-methylsulfanyl-2-propenenitrile (0.500 g, 0.6 mmol) was stirred in 2-amino-3,3-dimethylbutane (1 ml) for 48 h at 100° C. under nitrogen in a sealed flask. The reaction mixture was concentrated and the residue dissolved in dichloromethane, washed twice with 1N aqueous HCl, once with brine, and once with water. The organic phase was dried (sodium sulphate) and evaporated to afford 450 mg (80%) of the title compound as pale yellow crystals. Mp 177-180° C. 1H NMR (200 MHz, CDCl3): δ=0.89 (s, 9H), 1.04 (d, 3H), 1.40 (d, 6H), 2.97 (m, 1H), 3.27 (m, 1H), 7.50 (s, 2H), 7.67 (s, 1H), 9.16 (brs, 1H);
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10][CH2:11][C:12]([O:14]C)=[O:13])=[CH:2]1>O1CCCC1.[Li+].[OH-].ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1
Reactant: COC(=O)CSc1c[nH]c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)CSc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
Methyl 2-((1H-indol-3-yl)thio)acetate from Step A was dissolved in a mixture of tetrahydrofuran (20 mL) and 2.0 M aqueous LiOH (15 mL), then stirred vigorously at ambient temperature for 30 min. Tetrahydrofuran was removed in vacuo, the aqueous layer neutralized with 1.2 N HCl and extracted with CH2Cl2. The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo to produce an oily residue. Upon diluting the residue in dichloromethane a solid formed which was filtered and dried to yield the desired product (2.00 grams, 9.65 mmol, 38% yield over 2 steps). LCMS>99% at 254 nm, RT=1.02 min, m/z=208 (M+1).
Reaction SMILES: [C:1](=[O:13])([S:11][CH3:12])[O:2][CH:3](OC(=O)C(C)C)[CH3:4].[C:14]([OH:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1](=[O:13])([S:11][CH3:12])[O:2][CH2:3][CH2:4][O:21][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CSC(=O)OC(C)OC(=O)C(C)C
Reactant: O=C(O)c1ccccc1
Product: CSC(=O)OCCOC(=O)c1ccccc1

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyethyl) S-methyl thiocarbonate (2) and replacing isobutyric acid with benzoic acid in Step B affords O-(benzoyloxyethyl) S-methyl thiocarbonate (215) as an oil.
Reaction SMILES: [C:1]([N:9]1[CH2:12][CH:11]([CH2:13][O:14][C:15]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([F:27])[CH:16]=2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[CH3:39][S:40]([NH2:43])(=[O:42])=[O:41]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([N:9]1[CH2:12][CH:11]([CH2:13][O:14][C:15]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[CH:22][C:18]([C:19]([NH:43][S:40]([CH3:39])(=[O:42])=[O:41])=[O:20])=[C:17]([F:27])[CH:16]=2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CN(C(=O)c3ccccc3)C2)cc1F
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CN(C(=O)c3ccccc3)C2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.9 %

Procedure:
A mixture of 4-((1-benzoylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid (20 mg, 0.05 mmol), EDCI (21 mg, 0.10 mmol), DMAP (12 mg, 0.10 mmol) and methanesulfonamide (9 mg, 0.10 mmol) in DCM (5 mL) was stirred at room temperature for 18 h. The mixture was diluted with DCM (10 mL) and washed with HCl (2 N, 15 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by HPLC (20%-30% CH3CN in 0.1% NH4HCO3) to give target compound (4 mg, 17%) as a pale yellow solid. LCMS (ESI) Method A: RT=3.86 min, m/z: 446.5 [M+H]+. 1H-NMR (500 MHz, MeOH-d4,): δ 7.67-7.31 (m, 5H), 7.30 (d, J=8.5 Hz, 1H), 6.89 (d, J=13.0 Hz, 1H), 4.65-3.62 (m, 1H), 4.61-4.22 (m, 5H), 3.36 (s, 3H), 3.25-3.23 (m, 1H), 1.99-1.95 (m, 1H), 0.94-0.61 (m, 4H).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:8]([O:27][CH3:28])[CH:7]=1)C.[OH-].[K+].O>C(O)C>[CH3:28][O:27][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([OH:29])=[O:3])[CH:11]=[CH:10][C:9]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)OCC)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1OC
Yield: 68 %

Procedure:
The title compound is prepared by the procedure of Example 64 using 60 g of product from Example 66, 24.84 g of potassium hydroxide, 45 ml of water and 650 ml of ethyl alcohol. The reaction is heated at reflux temperature for 41 hours. The residue is recrystallized from methylene chloride/hexane to give 38 g of the desired product as cream needles.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:26])=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18]C(=O)OC(C)(C)C)[N:14]=[CH:15]3)=[CH:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCCl>[F:1][C:2]1[C:3]([CH3:26])=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1c(F)cncc1-c1cc2cnc(NC(=O)OC(C)(C)C)cc2cn1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(F)cncc1-c1cc2cnc(N)cc2cn1
Temperature: 40 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
A suspension of tert-butyl 7-(5-fluoro-4-methylpyridin-3-yl)-2,6-naphthyridin-3-ylcarbamate (50 mg, 0.14 mmol) in 1,2-dichloroethane (1 mL) was treated with trifluoroacetic acid (0.11 mL, 1.41 mmol), and the mixture was stirred at 40° C. for 3 hours. The mixture was concentrated in vacuo and then diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford the title compound as a bright yellow solid (36 mg, 98%), which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[N:27]=[CH:26][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[Cl:25])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:28][NH:29][CH3:30]>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:26]=[N:27][C:2]([N:29]([CH3:30])[CH3:28])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1
Reactant: Clc1ccccc1-n1ncnc1-c1cn2c(n1)-c1cnc(Br)cc1OCC2
Reactant: CNC
Product: CN(C)c1cc2c(cn1)-c1nc(-c3ncnn3-c3ccccc3Cl)cn1CCO2

Procedure:
Following the procedures of Examples 413 and 420, 9-bromo-2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine and dimethylamine were reacted to give 422. LC/MS (ESI+): m/z 408.1 (M+H)
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][C:14]1[CH:31]=[CH:30][C:29]2[C@@H:28]3[C@H:19]([C@H:20]4[C@@:24]([CH2:26][CH2:27]3)([CH3:25])[C:23](O)([C:32]([F:35])([F:34])[F:33])[CH2:22][CH:21]4[CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:18][CH2:17][C:16]=2[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>N1C=CC=CC=1>[CH2:6]([O:13][C:14]1[CH:31]=[CH:30][C:29]2[C@@H:28]3[C@H:19]([C@H:20]4[C@@:24]([CH2:26][CH2:27]3)([CH3:25])[C:23]([C:32]([F:34])([F:35])[F:33])=[CH:22][CH:21]4[CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:18][CH2:17][C:16]=2[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)C(=O)OCCCCC1CC(O)(C(F)(F)F)[C@@]2(C)CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@H]12
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)OCCCCC1C=C(C(F)(F)F)[C@@]2(C)CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@H]12
Temperature: 25 °C
Yield: 77.6 %

Procedure:
Phosphorylchloride (0.25 ml; 200 μmol) was added to a solution of 2,2-Dimethylpropionic acid 4-(3-benzyloxy-17-hydroxy-17-trifluoromethyl-estra-1,3,5(10)-trien-15-yl)-butylester (80.0 mg; 136 μmol) in pyridine (2.50 ml) and the resulting mixture is heated under reflux for 24 h. Then, the mixture was allowed to cool to RT, diluted with ice water and extracted with ether. The combined organic phases were dried over MgSO4 and the solvent was evaporated. The residue was purified by column chromatography (SiO2, DCM) yielding the title compound (60.0 mg, 78%) as colorless oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[CH2:22]([N:24]([CH2:39][CH3:40])[CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:34]([CH3:35])=[C:33]([CH:36]=O)[NH:32][C:31]=1[CH3:38])=[O:29])[CH3:23]>C(O)C.N1CCCCC1>[CH2:39]([N:24]([CH2:22][CH3:23])[CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:34]([CH3:35])=[C:33]([CH:36]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[NH:14][C:13]2=[O:19])[NH:32][C:31]=1[CH3:38])=[O:29])[CH3:40]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.9 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 2,4-dimethyl-5-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (75.6 mg, 56%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][C@@H:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)=[CH:4][CH:3]=1.[C:21]([C:25]1[O:29][N:28]=[C:27]([NH2:30])[CH:26]=1)([CH3:24])([CH3:23])[CH3:22].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CS(C)=O>[C:21]([C:25]1[O:29][N:28]=[C:27]([NH:30][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][N:9]3[CH2:14][CH2:13][O:12][C@@H:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:10]3)=[CH:6][N:7]=2)[CH:26]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: Clc1ccc(CN2CCO[C@@H](c3ccccc3)C2)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(Nc2ccc(CN3CCO[C@@H](c4ccccc4)C3)cn2)no1
Temperature: 60 °C
Yield: 24 %

Procedure:
2.73 mL of (S)-4-(6-Chloro-pyridin-3-ylmethyl)-2-phenyl-morpholine in DMSO(0.1M solution) was added to 63 mg of 5-tert-Butyl-isoxazol-3-ylamine. 900 L of sodium bis(trimethylsilyl)amide (1M solution in tetrahydrofuran) was added and the reaction heated overnight at 60° C. on an orbital shaker. The reaction was filtered through a fritted cartridge. Purification was accomplished by preparatory liquid chromatography to give the title compound in 24% yield. EI m/z 393=MH+
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][NH2:15])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1c[nH]c(-c2ccccc2)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCc1c[nH]c(-c2ccccc2)n1
Temperature: 2.5 °C
Yield: 77.2 %

Procedure:
To a solution of 2-[3-(2-phenyl-1H-imidazol-4-yl)-propyl]-isoindole-1,3-dione (4.16 g) in ethanol (50 ml) was added hydrazine hydrate (3.18 g). The reaction mixture was stirred under reflux for 4 h, cooled down to 0-5° C., and the precipitate was filtered off. The filtrate was concentrated, and the oily residue was quenched with cooled 1 N NaOH solution (20 ml) and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and concentrated to dryness to obtain 3-(2-phenyl-1H-imidazol-4-yl)-propylamine (1.95 g) as a yellow foam, which was sufficiently pure to be used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.Br[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4](=[O:8])[CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=c1cc(Br)cc[nH]1
Product: CC(C)(C)OC(=O)Cn1ccc(Br)cc1=O

Procedure:
4.9 g (28.4 mmol) of 4-bromopyridin-2(1H)-one and 1.2 eq. of tert-butyl 2-bromoacetate were reacted according to General Method 4B at 120° C. After aqueous work-up, the crude product was reacted further without further purification. Yield: 8.6 g (purity 91%, 95% of theory)
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH3:27][O:28][CH2:29]Cl.C(OCC)(=O)C>C1COCC1>[CH3:27][O:28][CH2:29][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COCCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(COC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (1.0 g, 4.07 mmol) in THF (20 mL) at −78° C. under nitrogen was added dropwise LDA (1.5 M in THF, 4.0 mL, 6.10 mmol). This solution was stirred for 1 hour at −78° C., after which methoxymethyl chloride (0.8 mL, 10.5 mmol) was added. The system was allowed to warm slowly to room temperature over 2 hours. The reaction was quenched with aqueous NH4Cl and extracted with ethyl acetate (3×50 mL). The organic layer was dried over a pad of silica gel, and the solvent removed under vacuum. The title compound was isolated by silica gel chromatography (5-10% ethyl acetate:hexanes) as a clear oil (830 mg, 69% yield). MS (ES+) [M+H]+=302.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:30])[C:11]3[C:16]4[N:17]=[C:18]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[N:19]=[C:20]([O:21][CH2:22][CH3:23])[C:15]=4[S:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[Li]CCCC.[CH:36](=[O:42])/[CH:37]=[CH:38]/[CH:39]=[CH:40]/[CH3:41]>C1COCC1>[CH2:22]([O:21][C:20]1[C:15]2[S:14][C:12]3[N:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH:36]([OH:42])/[CH:37]=[CH:38]/[CH:39]=[CH:40]/[CH3:41])=[CH:3][CH:4]=4)[N:9]=[C:10]([CH3:30])[C:11]=3[C:16]=2[N:17]=[C:18]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:19]=1)[CH3:23]
Reactant: C/C=C/C=C/C=O
Reactant: CCOc1nc(N2CCNCC2)nc2c1sc1nc(-c3ccc(Br)cc3)nc(C)c12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C/C=C/C=C/C(O)c1ccc(-c2nc(C)c3c(n2)sc2c(OCC)nc(N4CCNCC4)nc23)cc1
Temperature: -10 °C

Procedure:
200 mg (0.4 mmol) 7-(4-bromophenyl)-4-ethoxy-9-methyl-2-piperazin-1-yl-thieno[2,3-d:4,5-d′]dipyrimidine was mixed at −80° C. in 50 ml THF with 0.48 ml (1.2 mmol) 2.5 M BuLi solution. After 15 min at this temperature, 112 mg (1.2 mmol) (2E,4E) hexadienal was added. Subsequently, the reaction mixture was heated to −10° C. and the reaction was terminated by addition of 10 ml saturated NaHCO3. The organic solvent was removed and the aqueous phase was extracted with CH2Cl2. Following flash chromatographic purification (CH2Cl2/methanol, 8:2) 130 mg (63%) of the title compound was obtained. ESI-MS [m/z]: 503, melting point: 149-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15](=O)[CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN.[BH3-][C:21]#[N:22].[Na+]>[Ti+4]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:15]([NH:22][CH3:21])[CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Reactant: [BH3-]C#N
Agent: [Ti+4]
Agent: CN
Agent: [Na+]
Product: CNC(C)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 4.4 %

Procedure:
A mixture of 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanone (247 mg, 0.91 mmol) and methyl amine (455 μL, 2.0 M in THF, 0.91 mmol) was stirred at RT for 2 min. Titanium (IV) isoproxide (336 μL, 1.14 mmol) was then added. The viscous green/yellow solution was stirred at RT for 3 h. NaBH3CN solution (640 μL, 1.0 M in MeOH, 0.64 mmol) was added and the cloudy solution was stirred at RT for 16 h. The solution was quenched with saturated NaCl solution (3 mL), filtered, and washed with MeOH (50 mL). 6M HCl (20 mL) was added and the aqueous phase was washed with Et2O (2×20 mL). The pH of the aqueous phase was adjusted to pH=12 with 3M NaOH and washed with EtOAc (3×30 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated. To a solution of the crude amine in Et2O (3 mL) was added HCl (3 mL, 2.0 M in Et2O). The crude HCl salt was recrystallized from CH3CN (6 mL) at 110° c to give 1-(1-(3,4-dichlorophenyl)cyclohexyl)-N-methylethanamine (8 mg) as white crystals. HPLC Rt=8.90 min; 1H NMR (400 mHz, CD3OD) 7.57-7.53 (m, 2H), 7.33-7.31 (m, 1H), 3.15-3.13 (m, 2H), 2.61 (s, 3H), 2.45 (broad d, J=11.73 Hz, 1H), 2.30 (broad d, J=12.46, 1H), 1.59-1.51 (m, 5H), 1.31-1.08 (m, 6H); LC-MS 7.87 min, (M+1) 286 @ 8.10 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Br:35])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:26]=2[Br:35])=[CH:20][C:16]=1[C:17]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:18]
Reactant: OC1CCOC1
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Br)ccc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCOC1)c1cc(Oc2ccc(C(F)(F)F)cc2Br)ccc1Cl
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. A solution of 2-chloro-5-(2-bromo-4-trifluoromethylphenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-chloro-5-(2-bromo-4-trifluoromethylphenoxy)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[F:33])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27]3[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=3[F:33])[CH2:25][CH2:26]2)=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)C1(c2ccc(F)cc2Cl)CCCC1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4Cl)CCCC3)CC2)c1

Procedure:
Example 137 was prepared from 1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: ESMS m/e: 546.1 (M+H)+.