Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:19][CH2:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[O:18])=[CH:15][C:14]=1[O:22][CH2:23][CH:24]1[CH2:25][CH2:26]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)O)cc1OCC1CC1)S(C)(=O)=O
Reactant: O=C(CO)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCC(=O)OCc2ccccc2)cc1OCC1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)-benzoic acid (see for reference procedure Example 18, WO 2010/089107, which is incorporated herein by reference in its entirety) (2.5 g, 6.49 mmol), benzyl 2-hydroxyacetate (1.078 g, 6.49 mmol), EDC (3.73 g, 19.46 mmol) and DMAP (0.396 g, 3.24 mmol) were mixed in DCM (150 ml), and the resulting mixture was stirred at RT for 24 hours. Then the mixture was washed with HCl 1N and NaHCO3 sat. sol.; the organic layer was dried over Na2SO4, and the solvent was evaporated. The crude was sonicated in MeOH; 2-(benzyloxy)-2-oxoethyl 4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoate precipitated (2.6 g, 4.87 mmol, 75% yield, MS/ESI+ 556.0 [MNa]+), it was filtered and used as such in the following reaction without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].O>CN1C(=O)CCC1>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=2)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1nc(N)nc(Cl)c1C#Cc1ccc(N)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nc(N)nc(N2CCN(C(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
The title compound is synthesized according to general procedure GP7 starting from 5.0 g (19.3 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidin-2-ylamine and 3.94 g (21.2 mmol) N-Boc-piperazine using 2.94 mL (21.2 mmol) triethylamine in 30 mL NMP. Work up is performed by addition of 500 mL water to the reaction mixture and stirring for 30 min. The solid material is filtered off, washed with water (50 mL three times) yielding 7.25 g (17.7 mmol) of the desired product with sufficient purity.
Reaction SMILES: [CH:1]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:12][CH:11]=2)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:29][OH:30]>>[CH:1]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:12][CH:11]=2)=[N:29][OH:30])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1
Agent: Cl
Product: ON=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1

Procedure:
In analogy to the procedure of Example IV, the title compound is prepared from 12.9 g (35.9 mmol) of the compound from Example XIII and 3.75 g (53.9 mmol) of hydroxylamine hydrochloride.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH3:9])[C:4]([NH2:6])=[O:5])C.[Cl:10]O>C(OCC)(=O)C>[Cl:10][NH:6][C:4](=[O:5])[CH:3]([CH3:1])[CH2:7][CH2:8][CH3:9]
Reactant: OCl
Reactant: CCCC(CC)C(N)=O
Solvent: CCOC(C)=O
Product: CCCC(C)C(=O)NCl
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A stirred suspension of 2-ethyl valeramide (33.0 g, 286 mmol) in 220 ml of ethyl acetate was cooled to 0° and hypochlorous acid (55.25 g of 27.67% solution, 291 mmol) was added over 15 minutes. The cooling bath was removed and stirring continued for 1/2 hour. The organic phase was collected and dried (MgSO4) and the solvent was removed on a rotary evaporator to yield 32.8 g of N-chloro-2-methyl valeramide as a clear yellow liquid.
Reaction SMILES: [OH:1][C:2]1[C:12]2[N:11]=[CH:10][CH:9]3[CH2:13][CH2:14][CH2:15][N:8]3[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:17].[CH3:18][OH:19]>>[OH:1][C:2]1[C:12]2[NH:11][CH:10]([O:19][CH3:18])[CH:9]3[CH2:13][CH2:14][CH2:15][N:8]3[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1ccc2c(c1O)N=CC1CCCN1C2=O
Reactant: CO
Product: COC1Nc2c(ccc(C)c2O)C(=O)N2CCCC12
Reaction time: 72 h

Procedure:
5.5 mg of 2,3,5,11a-tetrahydro-9-hydroxy-8-methyl-1H-pyrrolo(2,1-C)(1,4)benzodiazepin-5-one was dissolved in 0.2 ml of hot methanol and allowed to stand at -20° C. for 3 days. Thus, 3.0 mg of 2,3,5,10,11,11a-hexahydro-9-hydroxy-11-methoxy-8-methyl-1H-pyrrolo(2,1-C)(1,4)benzodiazepin-5-one was obtained as a colorless crystal. Its infrared absorption spectrum just coincided with that of the product of Example 4.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[C:9]([CH2:25][CH3:26])[N:8]([C@@H:27]3[CH2:30][C@H:29]([CH2:31]O)[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>N1C=CC=CC=1>[CH2:18]([O:17][C:13]1[CH:12]=[C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([C@H:27]3[CH2:28][C@@H:29]([CH2:31][N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH2:30]3)[C:9]=2[CH2:25][CH3:26])[CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C1CCNC1
Reactant: CCc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CO)C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CN2CCCC2)C1

Procedure:
The title compound is prepared in a one pot reaction in analogy to Example 116 starting from 0.2 g (0.46 mmol) cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol of Example 124 and 0.18 g (0.92 mmol) p-toluenesulfonyl chloride in 2 ml dry pyridine followed by 2 ml pyrrolidine. The reaction is controlled by tlc. Analytical HPLC: tR=9.61 min (Grad 1); ES-MS: m/eo=482.0; NMR (DMSO-d6; not all signals reported): 8.12/s (1H); 6.9-7.5/several m's (6H), 7.05/“d” (1H); 6.95/s (1H); 6.92/“d” (1H); 5.4-6.0/b (NH2); 5.15/s (2H); 4.72/m (1H); 2.62/q (2H); 1.06/t (3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].O>CN(C=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[N:9][C:10]1=[O:14]
Reactant: ClCCCCBr
Reactant: Cc1cc(-c2cc[nH]c(=O)n2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2ccn(CCCCCl)c(=O)n2)ccn1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 26.3 %

Procedure:
To a solution of 4-(2-methyl-pyridin-4-yl)-1H-pyrimidin-2-one (256 mg, 1.37 mmol) in dry DMF (45 ml), 60% NaH (71 mg, 1.78 mmol) was added portionwise under inert atmosphere. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (305 mg, 1.78 mmol) was added and the mixture was stirred at room temperature for 1.5 hours and heated at 60° C. for 2 hours. Water was added and the mixture extracted with diethyl ether and with ethyl acetate. The organic layers were mixed together, dried (Na2SO4) and evaporated to afford 100 mg of the title compound that was used in the next step without further purification in the next step (27% yield).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH:16]1([CH2:19][O:20][C:21]2[C:22]([CH3:30])=[CH:23][C:24]([CH:27]([NH2:29])[CH3:28])=[N:25][CH:26]=2)[CH2:18][CH2:17]1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:29]([CH:27]([C:24]3[CH:23]=[C:22]([CH3:30])[C:21]([O:20][CH2:19][CH:16]4[CH2:18][CH2:17]4)=[CH:26][N:25]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)ncc1OCC1CC1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ncc1OCC1CC1
Yield: 73 %

Procedure:
The title compound is prepared in 73% yield (321 mg, colorless oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (344 mg, 1.24 mmol, Step-1 of Intermediate-1) and 1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (300 mg, 1.24 mmol, Amine-73, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: COC(=O)CO[C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][N:26]2[C@H:30]([CH3:31])[C@H:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:28][C:27]2=[O:38])[CH:7]=1.Br.[C:41]([OH:44])(=[O:43])[CH3:42]>>[OH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:42][C:41]([OH:44])=[O:43])=[CH:7][C:8]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:16]=1[CH2:25][N:26]1[C@H:30]([CH3:31])[C@H:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:28][C:27]1=[O:38]
Reactant: CC(=O)O
Reactant: COC(=O)COc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1
Agent: Br
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Oc1cc(CC(=O)O)ccc1O
Temperature: 100 °C

Procedure:
{4-Methoxy-3-[2-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-trifluoromethyl-phenoxy]-phenoxy}-acetic acid methyl ester (2.0 g, 3.78 mmol) was treated with a 1:1 mixture of 48% hydrogen bromide and acetic acid, and the reaction was heated to 100° C. overnight. The mixture was concentrated to dryness, and then worked-up with EtOAc and saturated aqueous NaHCO3. The crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Li]CCCC.[CH2:17]1[O:20][CH:18]1[CH3:19]>C1COCC1.CCCCCC>[F:9][C:8]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:17][CH:18]([OH:20])[CH3:19]
Reactant: FC(F)(F)c1ccccc1I
Reactant: CC1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
General Procedure HH: To a solution of 1-iodo-2-(trifluoromethyl)benzene (1.5 g, 5.5 mmol) in THF (10.0 mL) was added 2.5 M of n-BuLi in hexane (2.2 mL) at −78° C. and stirred for 10 min. Propylene oxide (370 mg, 6.4 mmol) was added to the reaction mixture at −78° C. and slowly warmed to rt. The reaction mixture was stirred for an additional 30 min. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to give a yellow oil. The material was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to yield the desired product as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ=1.30 (d, J=6.1 Hz, 3H), 1.46 (d, J=4.3 Hz, 1H), 2.82-3.06 (m, 2H), 4.03-4.12 (m, 1H), 7.32-7.38 (m, 1H), 7.41-7.45 (m, 1H), 7.48-7.53 (m, 1H), 7.67 (d, J=8.1 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:3][C@@H:4]([CH:11]([CH3:13])[CH3:12])[CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>C(Cl)Cl>[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([N:3]([CH2:1][CH3:2])[C@@H:4]([CH:11]([CH3:12])[CH3:13])[CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)=[O:20])=[CH:17][CH:16]=1
Reactant: CCN[C@H](CN1CCCC1)C(C)C
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: CCN(C(=O)c1ccc(Br)cc1)[C@H](CN1CCCC1)C(C)C
Yield: 14.6 %

Procedure:
To a solution of (S)—N-ethyl-3-methyl-1-(pyrrolidin-1-yl)butan-2-amine (0.1 g, 0.54 mmol) (for synthesis, see e.g. EP254545) in DCM (2 mL) was TEA (0.075 mL, 0.54 mmol) and 4-bromobenzoyl chloride (0.119 g, 0.54 mmol) added. The resultant mixture was stirred at rt overnight. The mixture was washed with H2O (2 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (29 mg, 15%). Mixture of rotamers: 1H NMR (400 MHz, CD3OD) δ 0.77-1.13, 1.30, 1.66-2.06, 2.26-2.59, 2.62-2.91, 3.00-3.29, 3.43-3.69, 7.27-7.42, 7.52-7.70. Total no of protons: 27. HRMS (M+H)+: calculated 367.1385. found 367.1384.
Reaction SMILES: C(OC([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]=[CH2:18])[CH:11]=[CH:10]2)C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl>C(O)C>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]=[CH2:18])[CH:11]=[CH:10]2
Reactant: C=Cc1ccc2cc(OC(C)OCC)ccc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCO
Product: C=Cc1ccc2cc(O)ccc2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
18 g of 6-(1-Ethoxy ethoxy)-2-vinylnaphthalene (0.0743 mol) was dissolved in 80 mL of ethanol. To this was added 1.6 g of pyridinium p-toluenesulfonate (0.0064 mol). The reaction mixture was stirred at 50° C. After 3 h, TLC analysis (silica, CH2Cl2) indicated that the reaction was over. The reaction mixture was cooled down to room temperature and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, CH2Cl2) to yield 11.15 g of pure 6-hydroxy-2-vinylnaphthalene (62%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[C:38]([O:39][CH3:40])=[CH:37][C:27]([CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[C:26]([F:41])[CH:25]=1.C(O)(C(F)(F)F)=O>>[F:41][C:26]1[CH:25]=[C:24]([NH:23][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[NH:13][CH3:14])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=2)[C:38]([O:39][CH3:40])=[CH:37][C:27]=1[CH2:28][P:29](=[O:36])([O:30][CH2:31][CH3:32])[O:33][CH2:34][CH3:35]
Reactant: CCOP(=O)(Cc1cc(OC)c(N)cc1F)OCC
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1cc(OC)c(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)cc1F)OCC
Yield: 54 %

Procedure:
A solution of 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 104A, 75.0 mg, 0.227 mmol) and diethyl (4-amino-2-fluoro-5-methoxybenzyl)phosphonate (Compound 130A, 79.0 mg, 0.271 mmol) in TFE (1.1 mL) was charged with TFA (77.3 mg, 0.678 mmol). The reaction mixture was irradiated on the microwave at 105° C. for 30 min. The reaction mixture was concentrated under reduced pressure to yield a yellow oil. The reaction was purified by silica gel chromatography on the combi-flash Rf system using EtOAc/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid, 71.3 mg (54% yield). 1H NMR (DMSO-d6, 400 MHz): δ=1.20 (t, J=7.07 Hz, 6H), 2.77 (d, J=4.55 Hz, 3H), 3.16-3.25 (m, 2H), 3.79 (s, 3H), 3.95-4.04 (m, 4H), 7.01 (d, J=5.05 Hz, 1H), 7.10-7.17 (m, 1H), 7.42 (t, J=7.58 Hz, 1H), 7.70 (d, J=7.58 Hz, 2H), 8.40 (br. s., 1H), 8.44 (s, 1H), 8.67 (s, 1H), 8.73 (d, J=3.79 Hz, 1H), 11.41 (s, 1H). MS (ES+): m/z 586.19 [MH+] (TOF, polar).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:38]=[CH:37][C:4]=1[CH2:5][N:6]([CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:12]=1.[CH3:45][O:46][C:47](=[O:50])[CH2:48]Br.C(N(C(C)C)CC)(C)C>CO>[CH3:45][O:46][C:47](=[O:50])[CH2:48][N:20]1[CH2:19][CH2:18][N:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][N:6]([CH2:5][C:4]3[CH:37]=[CH:38][CH:39]=[C:40]([C:41]([F:42])([F:44])[F:43])[C:3]=3[Cl:2])[CH2:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:12]=2)[CH2:22][CH2:21]1
Reactant: FC(F)(F)c1cccc(CN(CCCOc2cccc(N3CCNCC3)c2)CC(c2ccccc2)c2ccccc2)c1Cl
Reactant: COC(=O)CBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)CN1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)c2)CC1
Temperature: 50 °C

Procedure:
To a solution of (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-piperazin-1-yl-phenoxy)-propyl]-amine hydrochloride (114 mg, 0.187 mmol—Example 168) in methanol (15 mL) was treated with bromo-acetic acid methyl ester (57 mg, 0.375 mmol) and diisopropyl-ethyl-amine (48 mg, 0.375 mmol). The resulting solution was heated at 50° C. for 3 hours, cooled to room temperature, and concentrated. The crude material was dissolved in EtOAc and washed with water (1×). The organic layer was then washed with brine (1×), dried over sodium sulfate, and filtered. The EtOAc was concentrated and the sample was dried under vacuum to title compound as an oil (99 mg, 78%). MS(ES) m/e 622.2 ([M−COOCH3]+).
Reaction SMILES: C(O)=O.[NH2:4][C:5]1[C:10]([OH:11])=[CH:9][N:8]=[C:7]([C:12]2[C:13]3[CH2:27][CH2:26][CH2:25][C:14]=3[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:16]=2)[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[C:36]1[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][N:39]=[CH:38][CH:37]=1>CN(C=O)C>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:15]1[C:14]2[CH2:25][CH2:26][CH2:27][C:13]=2[C:12]([C:7]2[N:6]=[C:5]([NH:4][C:36]3[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][N:39]=[CH:38][CH:37]=3)[C:10]([OH:11])=[CH:9][N:8]=2)=[N:16]1
Reactant: CCOC(=O)c1cnccc1Cl
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3c2CCC3)ncc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnccc1Nc1nc(-c2nn(Cc3ccccc3F)c3c2CCC3)ncc1O
Temperature: 50 °C

Procedure:
3.00 g of formic acid—4-amino-2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]pyrimidin-5-ol (1:1) 1-8-1 (9.22 mmol, 1.00 eq.) were dissolved in 300 mL DMF, 6.37 g potassium carbonate (46.1 mmol, 5.00 eq) were added and under nitrogen atmosphere 2.05 g ethyl 4-chloronicotinate hydrochloride (1:1) (9.22 mmol, 1.00 eq.) were added. The reaction mixture was stirred at 50° C. over night, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography twice to provide 100 mg (0.21 mmol, 2.2%) of analytically pure target compound.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11](Cl)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]([CH3:28])P(=O)(N(C)C)N(C)C>>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([N:19]([CH3:28])[CH3:18])=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2s1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Product: CN(C)c1cc2nc(C(C)(C)C)sc2cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A solution of 16.2 g of 2-tert-butyl-5-chloro-6-nitrobenzothiazole, described in Example 5, in 150 ml hexamethyl phosphoric triamide is heated at 200° for 10 hours and poured into ice-water. The liquid separated is extracted with ether, dried over anhydrous sodium sulphate and the ether is evaporated under reduced pressure to give a red oil which is purified by silica gel column chromatography. Elution with benzene hexane (1:1) gives 2-tert-butyl-5-[N,N-dimethyl]amino-6-nitrobenzothiazole, melting at 65°-68°.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[CH:6][C:3]=1[CH:4]=O.[O:12]=[C:13]([CH3:16])[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:11][C:7]1[CH:6]=[C:3]2[C:2](=[C:9]([CH3:10])[CH:8]=1)[O:1][CH2:15][C:14]([C:13](=[O:12])[CH3:16])=[CH:4]2
Reactant: C=CC(C)=O
Reactant: Cc1cc(C)c(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)C1=Cc2cc(C)cc(C)c2OC1

Procedure:
1.50 g (10 mmol) of 2-hydroxy-3,5-dimethylbenzaldehyde together with 0.66 g (10 mmol) of 3-oxo-1-butene are added at room temperature to a suspension of 0.14 g (1 mmol) of potassium carbonate in 50 ml of 2-butanone. The mixture is brought to reflux with stirring and this temperature is maintained for 90 minutes. The reaction medium is evaporated on a water bath under vacuum, and the residue is taken up with 100 ml of water and extracted 3 times with 75 ml of diethyl ether. The organic phases are combined, washed to neutrality with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated on a water bath under vacuum, and chromatographed on a column of silica (70-230 mesh), eluting with dichloromethane.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].IC.[C:33](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][N:17]([CH3:33])[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CI
Product: CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with iodomethane and cesium carbonate in N,N-dimethylacetamide to give N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-N-methyl-2-trifluoromethyl-benzenesulfonamide as a light yellow semi-solid. MS: 506.9 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH:6]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.P(Cl)(Cl)([Cl:22])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:22])[CH:6]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1
Reactant: O=c1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cccc(-c2cc(Cl)nc3ccc(Br)cc23)c1
Yield: 100 %

Procedure:
A mixture of intermediate 4 (0.16 mol) in phosphoryl chloride (500ml) was stirred and refluxed for one night. The mixture was evaporated till dryness, the residue was taken up in ice and water, alkalized with NH4OH and extracted with DCM. The organic layer was decanted, dried (MgSO4), filtered off and evaporated, yielding 56 g (100%) of 6-bromo-2-chloro-4-(3-chlorophenyl)quinoline, mp.125° C. (intermediate 5).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[N:32]1([C:38]2([CH2:44][NH2:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:45][CH2:44][C:38]5([N:32]6[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]6)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: NCC1(N2CCCCC2)CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNCC5(N6CCCCC6)CCCCC5)c4)cc23)CC1
Yield: 34.7 %

Procedure:
Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol), 1-[1-(1-piperidinyl)cyclohexyl]methanamine (17 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give the title compound (18.7 mg, 27%).