Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C>[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:61]=[C:60]4[C:56]([CH:57]=[N:58][NH:59]4)=[C:55]([NH:62][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=4)[CH:54]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1
Reactant: Cc1cccc(C(=O)O)c1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
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
Product: Cc1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)c1
Reaction time: 0.08 h

Procedure:
3-Methylbenzoic acid (60 mg, 0.44 mmol) was treated with HATU (168 mg, 0.44 mmol) in DMF (0.750 mL) and DIPEA (0.15 mL, 0.86 mmol). The mixture was shaken for five minutes prior to treatment with 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.2 mmol) in DMF (0.350 mL) and was then left to stand at room temperature for 16 hrs. Solvent was removed in vacuo and the product re-dissolved in chloroform (0.3 mL) prior to application on to a pre-conditioned (methanol then chloroform) NH2 cartridge (1 g). Product was eluted after 2 hr with ethyl acetate/methanol (1:1, 3.2 mL), and concentrated under a stream of nitrogen using blow down apparatus. Purification by MDAP (Method C) afforded the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[O:21]1[C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=[N:22]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:26]([C:25]2[O:21][N:22]=[CH:23][CH:24]=2)=[O:27])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccno1
Agent: Cl
Product: O=C(CNC(=O)c1ccno1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and isoxazole-5-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=[C:9]1[NH2:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@H:11]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:10]=[C:9]1[NH:25][C:38](=[O:39])[C:37]1[CH:41]=[CH:42][C:34]([F:33])=[CH:35][CH:36]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1C(N)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C(NC(=O)c2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A mixture of 124 (200 mg, 0.593 mmol), triethylamine (0.082 mL, 0.583 mmol), 4-dimethylaminopyridine (10 mg), and 4-fluorobenzoyl chloride (0.063 mL, 0.533 mmol) in dichloromethane (2 mL) is stirred at RT for 0.5 h. The solution is diluted with dichloromethane and washed with NaHCO3, brine, and then dried (MgSO4). The mixture is filtered, the filtrate evaporated, and residue purified by chromatography on silica gel; gradient elution with heptane:EtOAc (70:30-60:40) gives 123 mg of the product 125. 1H NMR (CDCl3) δ 10.00 (s, 1 H), 8.50-8.35 (m, 2 H), 7.20-6.85 (m, 12 H), 6.55-6.40 (m, 2 H), 1.20 (s, 9 H); MS: m/z 460 (M++1).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[NH2:26][CH2:27][CH:28]([OH:30])[CH3:29]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:26][CH2:27][CH:28]([OH:30])[CH3:29])=[O:13])[CH2:8]2
Reactant: CC(O)CN
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: CC(O)CNc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccccc1

Procedure:
5-(2-Hydroxy-propylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 1-amino-2-propanol. Mass spectrum (ES) MH+=395.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].N[C@H](C(OC(C)(C)C)=O)CC(O)=O.C(OC(=O)[C@@H](N[C:40](=[O:45])[CH2:41][CH2:42][CH:43]=[CH2:44])CC(O)=O)(C)(C)C>>[C:11]([O:10][C:8](=[O:9])[C@@H:2]([NH:1][C:40](=[O:45])[CH2:41][CH2:42][CH:43]=[CH2:44])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Reactant: C=CCCC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)[C@@H](N)CC(=O)O
Product: C=CCCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C

Procedure:
A mixed crude product B (9.28 g, 100%) of (S)-5-(tert-butoxy)-5-oxo-4-(pent-4-enamido)pentanoic acid (Compound 1b-II) and pent-4-enoic acid (1:0.8) was obtained using (S)-4-amino-5-(tert-butoxy)-5-oxopentanoic acid (Compound 1a-II, 5.00 g, 24.2 mmol) in place of (S)-3-amino-4-(tert-butoxy)-4-oxobutanoic acid (Compound 1a-I) under the same conditions as in the preparation example for Compound 1b-I.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=2)=[CH:4][CH:3]=1.[CH3:37][S:38][CH2:39][CH2:40][CH:41]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([CH2:41][CH2:40][CH2:39][S:38][CH3:37])[CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:33])([F:32])[F:34])[CH:24]=2)=[CH:6][CH:7]=1
Reactant: CSCCC=O
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(CCCSC)CC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 104, the title compound N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3-methylsulfanyl-propyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 3-(methylthio)propionaldehyde instead of acetone and was obtained as a colorless oil. MS m/e: 612.1 [M]+.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C.[OH-].[Na+]>C1C=CC=CC=1.NCCC(O)=O.O>[C:1](/[C:3](=[CH:9]\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1ccccc1
Agent: NCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)/C(C#N)=C/c1ccccc1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
A mixture containing 4.0 mL (37.6 mmoles) of ethyl cyanoacetate, 3.95 g (37.2 mmoles) of benzaldehyde, 20 mg of β-alanine, and 1.00 mL of glacial acetic acid in 35 mL of benzene was heated at reflux for 3 hours with continuous azeotropic removal of water by means of a Dean-Stark trap. The product was isolated by cooling the mixture to room temperature, pouring it into 75 mL of 2:1 (v/v)1M aqueous NaOH:saturated brine, and extraction with ether. The organic extracts were washed with 75 mL of 2:1 (v/v) 1M aqueous NaOH:saturated brine, 10% aqueous sodium chloride solution, then were dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the ether and benzene by evaporation at reduced pressure afforded 6.88 g (92% yield) of crystalline cyanoester 1: mp 49°-50° C.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[S:30](Cl)([CH3:33])(=[O:32])=[O:31].OS(O)(=O)=O>N1C=CC=CC=1.O>[OH:27][CH:17]1[CH:16]2[CH:15]([CH2:14][CH:13]([OH:28])[C:12]3([CH3:29])[CH:11]2[CH2:10][CH2:9][CH:8]3[CH:2]([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:20]2([CH3:26])[CH:19]([CH2:24][CH:23]([O:25][S:30]([CH3:33])(=[O:32])=[O:31])[CH2:22][CH2:21]2)[CH2:18]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: O
Product: CC(CCC(=O)O)C1CCC2C3C(O)CC4CC(OS(C)(=O)=O)CCC4(C)C3CC(O)C12C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
100 g of cholic acid are dissolved in 500 ml of pyridine and 23.1 ml of mesyl chloride are added dropwise over a period of 30 minutes at 0° C. The mixture is stirred at RT for 3 hours, then poured into a solution of 400 ml of H2SO4 in 3 l of water at 0° C. and extracted 4 times using 750 ml of EA each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. The residue is crystallized using diisopropyl ether and 117.1 g are obtained; m.p. 121° C. (with decomposition).
Reaction SMILES: [Br:1][CH:2]1[C:7](=[O:8])[C:6]([CH:9](O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][N:4]=[CH:3]1.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>ClCCl>[CH2:9]([CH:6]1[C:7](=[O:8])[C:2]([Br:1])=[CH:3][N:4]=[CH:5]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1C(C(O)c2ccccc2)=CN=CC1Br
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(Br)=CN=CC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 3-bromo-5-(hydroxyl-phenyl-methyl)pyridin-4-one 11 (0.125 g, 91 mmol), TFA (16 mL) and Et3SiH in anhydrous dichloromethane (30 mL) was stirred at rt for 10 h [Borzilleri, et al., U.S. Pat. 20050245530]. The reaction mixture was concentrated in vacuo and the residue purified by flash column chromatography on silica gel (dichloromethane:methanol, 98:2). Yield 0.081 g (69%), white solid. 1H NMR (MeOH— d4, 500 MHz): δ 8.12 (s, 1H), 7.47 (s, 1H), 7.29-7.17 (m, 5H), 3.83 (s, 2H). 13C NMR (MeOH—d4, 125 MHz): δ 175.2, 140.7, 139.5, 136.9, 130.8, 130.0, 130.0, 129.5, 129.5, 127.3, 114.1, 34.9.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:10][C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13](=[O:15])[C:20]=2[CH:21]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(Oc2ccccc2C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CCCCOc1ccc2oc3ccccc3c(=O)c2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Finally, 2-butoxyxanthen-9-one (S-14) was synthesized. A stirred suspension under argon of 2-(4-butoxyphenoxy)benzoic acid (8.2 g, 29 mmol) in acetic anhydride (50 mL) was treated with 2.8 g (29 mmol) of concentrated sulfuric acid, and then held at 80° C. for 3 h. The mixture was cooled to ambient, and then poured onto 500 g of ice. The precipitated crude product was collected, washed with water, and air dried. The product was purified by column chromatography followed by recrystallization from 50% aqueous ethanol. A white powder was obtained. 1H NMR (CDCl3): δ 1.00 (t, 3H), 1.5 (m, 2H), 1.85 (m, 2H), 4.08 (t, 2H), 7.3-7.5 (m, 4H), 7.7 (m, 2H), 8.36 (d, 1H).
Reaction SMILES: [C:1]1(=[O:10])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.C(N(CC)CC)C.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>O1CCCC1.CN(C)C1C=CN=CC=1>[C:22]([O:21][C:19]([N:2]1[CH2:3][CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[C:1]1=[O:10])=[O:18])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C1NCC2CCCCC12
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2CCCCC2C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 3 (835 mg, 6 mmol) in suspension in tetrahydrofuran (7 mL) was successively added, under an argon atmosphere, 4-dimethylaminopyridine (18.3 mg; 0.15 mmol), triethylamine (0.84 mL; 6 mmol) and BOC2O (2.62 g; 12 mmol). The reaction mixture was stirred at room temperature for 3 days. The solvent was removed under vacuum. The residue was diluted with diethyl ether (20 mL) and washed with water (2×10 mL). The phases were separated, and the organic phase was dried over MgSO4 and concentrated. The crude oil was purified over silica gel chromatography (ether/heptane 1:1) to give 4 (986 mg; 4.1 mmol; 70%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[C:4]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:3]=1.[NH:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:15][C:14]([NH:13][C:4]1[N:5]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:7]=[C:2]([N:18]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1)([CH3:17])[CH3:16]
Reactant: C1CNCCNC1
Reactant: CC(C)(C)Nc1cc(Cl)nc(NC(C)(C)C)n1
Product: CC(C)(C)Nc1cc(N2CCCNCC2)nc(NC(C)(C)C)n1
Yield: 55.3 %

Procedure:
By reacting 4-chloro-2,6-bis(1,1-dimethylethylamino)-pyrimidine with hexahydro-1H-1,4-diazepine as described in Example 4, the title product is obtained in a yield of 55.3%, m.p.: 127°-132° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Br:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([NH2:14])=[O:13].[O:15]=[C:16](Cl)OC(Cl)(Cl)Cl.O>O1CCOCC1>[Br:11][C:7]1[CH:8]=[CH:9][C:10]2[C:2]3[NH:1][C:16](=[O:15])[NH:14][C:12](=[O:13])[C:3]=3[NH:4][C:5]=2[CH:6]=1
Reactant: NC(=O)c1[nH]c2cc(Br)ccc2c1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)c2[nH]c3cc(Br)ccc3c2[nH]1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
12.2 g (58 mmol) 3-amino-6-bromo-1H-indole-2-carboxylic acid amide was suspended in 50 ml dioxan, and, after the addition of 11.7 ml (96 mmol) diphosgene, the suspension was refluxed for 2 h. Having cooled down to room temperature, 20 ml water was carefully added and the precipitate was subsequently sucked off. 13.4 g (99%) 7-bromo-1H-pyrimido[5,4-b]indole-2,4(3H,5H)-dione was obtained. ESI-MS [m/z]: 278, 280 [M−H]−
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22]3[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=3[O:20][CH2:19][C:18]2=[O:29])[CH2:11][CH2:10]1.[O:30]=[C:31]1[CH2:36][S:35][C:34]2[CH:37]=[CH:38][C:39]([CH:41]=O)=[N:40][C:33]=2[NH:32]1.C([BH3-])#N.[Na+]>>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]2[O:20][CH2:19][C:18](=[O:29])[N:17]([CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][CH:9]([NH:8][CH2:41][C:39]4[CH:38]=[CH:37][C:34]5[S:35][CH2:36][C:31](=[O:30])[NH:32][C:33]=5[N:40]=4)[CH2:14][CH2:13]3)[C:22]=2[CH:23]=1
Reactant: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CS4)CC1)C(=O)CO2
Yield: 29 %

Procedure:
4-[2-(4-aminopiperidin-1-yl)ethyl]-6-methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 46) (0.2 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (WO 2004/058144) (42 mg, 0.22 mmol) and sodium cyanoborohydride (23 mg, 0.36 mmol) were reacted as described under Example 21 to give 28 mg (32%) of product as a dry film.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[NH2:19][CH2:20][C:21]1[C:22](=[O:31])[NH:23][C:24]([CH3:30])=[CH:25][C:26]=1[CH2:27][CH2:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][CH2:20][C:21]2[C:22](=[O:31])[NH:23][C:24]([CH3:30])=[CH:25][C:26]=2[CH2:27][CH2:28][CH3:29])=[O:18])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)[C:9]=2[CH:10]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Reactant: O=C(O)c1cc(Cl)cc2c1cnn2C1CCCC1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Cl)cc2c1cnn2C1CCCC1

Procedure:
The title compound was prepared in the same manner as described for example 3 (step c) from 6-chloro-1-cyclopentyl-1H-indazole-4-carboxylic acid (0.12 g, 0.453 mmol) and 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (0.128 g, 0.680 mmol). The final product was collected as 0.170 g (86%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.33 Hz, 3H), 1.45-1.57 (m, 2H), 1.61-1.74 (m, 2H), 1.80-1.92 (m, 2H), 1.92-2.03 (m, 2H), 2.05-2.19 (m, 5H), 4.36 (d, J=5.05 Hz, 2H), 5.21 (t, J=7.07 Hz, 1H), 5.91 (s, 1H), 7.59 (d, J=1.52 Hz, 1H), 8.06 (s, 1H), 8.37 (s, 1H), 8.62 (t, J=4.80 Hz, 1H), 11.55 (s, 1H); LC-MS (ES) m/z=426.7 [M+H]+
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: NCCc1ccccc1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: FC(F)(F)c1cc2c(NCCc3ccccc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-3-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-phenethylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[S:45](Cl)(=[O:47])=[O:46])#[N:38].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[S:45]([N:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:10][CH:11]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:18]=1)(=[O:47])=[O:46])#[N:38]
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: c1cc(CNc2ccc(OCCN3CCCC3)cc2)cc(OC2CCCCO2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1S(=O)(=O)N(Cc1cccc(OC2CCCCO2)c1)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.091 g, 0.23 mmol) and triethylamine (0.097 mL, 0.69 mmol) in 2 mL methylene chloride was added 2-cyanobenzenesulfonyl chloride (0.093 g, 0.46 mmol). The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was washed with an additional 2 mL of methylene chloride. The combined organic layers were concentrated to afford the title compound of Step A.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C@@H:6]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[NH:7][C:8](=[O:23])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)C.[OH-].[Na+]>CCO>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C@@H:6]([NH:7][C:8](=[O:23])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][NH:16][C:15]=3[N:14]=2)[CH2:5][C:4]([OH:30])=[O:3])[CH:25]=1
Reactant: CCOC(=O)C[C@H](NC(=O)CCCCc1ccc2c(n1)NCCC2)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C[C@H](NC(=O)CCCCc1ccc2c(n1)NCCC2)c1cccnc1
Reaction time: 2 h

Procedure:
To a solution of 1-8 (0.1847 mmol) in EtOH (2 mL) was added 1N NaOH (0.250 ml, 0.250 mmol). After stirring for 2 h, the solvents were evaporated and the residue was chromatographed (silica gel, 15:10:1:1 ethyl acetate/EtOH/water/NH4OH) to give 1-9 as a white solid.
Reaction SMILES: COC(C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=CN=1)=O.ClC1C=C([C:30]2[CH:31]=[C:32]([CH3:49])[C:33]([C:36]([N:38]3[CH2:43][CH2:42][CH:41]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH2:40][CH2:39]3)=[O:37])=[N:34][CH:35]=2)C=CC=1Cl.[F:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][C:52]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl>[F:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][C:52]=1[C:30]1[CH:31]=[C:32]([CH3:49])[C:33]([C:36]([N:38]2[CH2:39][CH2:40][CH:41]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[CH2:42][CH2:43]2)=[O:37])=[N:34][CH:35]=1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cnc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1F
Agent: Cl[Pd]Cl
Agent: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cc(C(F)(F)F)ccc2F)cnc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 1A, (5-bromo-3-methyl-pyridin-2-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (see example 28) was reacted with 2-fluoro-5-trifluoromethyl-phenyl-boronic acid, (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) and sodium carbonate in dioxane/water to give the title compound as brown amorphous solid. MS: 436.3 (MH+).
Reaction SMILES: [CH:1]1([C:7]([OH:31])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:32]>ClCCl>[ClH:32].[CH:25]1([C:7]([OH:31])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)C(O)(c2ccccc2)C2CCCCC2)CC1
Agent: Cl
Solvent: ClCCl
Product: O=C(OCC1CCNCC1)C(O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
tert-Butyl 4-((2-cyclohexyl-2-hydroxy-2-phenylacetyloxy)methyl)-piperidine-1-carboxylate (1.10 g, 2.55 mmol) was dissolved in hydrochloric acid (5 mL, 4 M solution in dioxane) and dichloromethane (5 mL). The reaction mixture was stirred at RT for 3 hours and concentrated under reduced pressure to afford the title compound (970 mg, >100%) that was used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH3:11][C@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH3:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1
Reactant: C[C@H]1CCCN1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1CCCN1c1cccc([N+](=O)[O-])c1
Yield: 90.7 %

Procedure:
A mixture of 1-bromo-3-nitrobenzene (1.43 g, 7.06 mmol), (S)-2-methylpyrrolidine (0.5 g, 5.88 mmol), Pd2(dba)3 (0.34 g, 0.59 mmol), X-Phos (0.56 g, 1.18 mmol) and sodium carbonate (1.77 g, 16.74 mmol) in the mixture of 1,4-dioxane (20 mL) and water (20 mL) was heated to reflux for 16 hours. Then water was added, extracted with ethyl acetate and organic layer washed brine dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to give (S)-2-methyl-1-(3-nitrophenyl)pyrrolidine (1.1 g, 91%) as red solid. LC-MS: 207 [M+H]+, tR=1.77 min.