Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C@@H:8]([S:10][C:11]2[N:12]=[C:13]([NH:22][C@H:23]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][OH:25])[C:14]3[S:19][C:18]([O:20]C)=[N:17][C:15]=3[N:16]=2)[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1>[Cl-].[Na+].O>[F:1][C:2]1[C:3]([C@@H:8]([S:10][C:11]2[N:12]=[C:13]([NH:22][C@@H:23]([CH2:24][OH:25])[CH2:26][CH:27]([CH3:28])[CH3:29])[C:14]3[S:19][C:18](=[O:20])[NH:17][C:15]=3[N:16]=2)[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1nc2nc(S[C@@H](C)c3ncccc3F)nc(N[C@@H](CO)CC(C)C)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@H](CO)Nc1nc(S[C@@H](C)c2ncccc2F)nc2[nH]c(=O)sc12
Temperature: 50 °C

Procedure:
The title compound was prepared from (2R)-2-[(5-{[(1S)-1-(3-fluoropyridin-2-yl)ethyl]thio}-2-methoxy[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol using General method D, except that the reaction mixture was heated to 50° C. for 1.5 h. After complete reaction the reaction mixture was diluted with brine and extracted with DCM (three times). The combined organic extracts were dried over magnesium sulphate and concentrated in vacuo. The product was purified by flash column chromatography (eluent DCM: methanol gradient) followed by preparative HPLC to yield 20 mg of the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[S:5]1[CH:9]=[CH:8][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6]1.[Br:15]Br>ClCCl>[Br:15][C:9]1[S:5][CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=1
Reactant: BrBr
Reactant: CCOC(=O)c1ccsc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)c1csc(Br)c1
Temperature: 0 °C
Yield: 57.1 %

Procedure:
20 g (147 mmol) of aluminum chloride are added portionwise to a solution of 10 g (67 mmol) of ethyl thiophene-3-carboxylate in 160 ml of dichloromethane, cooled beforehand to 0° C. The reaction medium is warmed to room temperature and a solution of 4 ml (73 mmol) of bromine in 10 ml of dichloromethane is then added. After reaction for 50 minutes at room temperature, the reaction medium is poured into a water+ice mixture and extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a 9/1 heptane/ethyl acetate mixture. 9 g (57%) of ethyl 5-bromothiophene-3-carboxylate are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=3)[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:34]([NH:38][S:39]([C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=1)(=[O:41])=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([NH:38][S:39]([C:42]1[CH:47]=[C:46]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=4)[CH:11]=[C:10]([C:30]([F:32])([F:31])[F:33])[N:9]=3)[CH:3]=2)[CH:45]=[CH:44][CH:43]=1)(=[O:41])=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-{4-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidin-2-yl}-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.55) (0.38 g, 0.69 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.23 g, 0.89 mmol) according to the general procedure VI. Obtained as light yellow solid (0.45 g), which was subsequently deprotected.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:4]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[N:3]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]([F:8])([F:10])[F:9])[N:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:13][CH:12]=2)[N:3]=1
Reactant: Cc1cc(C(F)(F)F)n(-c2ccc(O)cc2)n1
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: Cc1cc(C(F)(F)F)n(-c2ccc(OCCN3CCCCC3)cc2)n1
Yield: 55 %

Procedure:
The title compound was prepared from 4-(3-Methyl-5-trifluoromethyl-pyrazol-1-yl)-phenol (0.1 g, 0.42 mmol) and 1-(2-chloroethyl)piperidine hydrochloride (0.16 g, 0.88 mmol) using the general procedure C with a yield of 55% (80 mg); 1H NMR (400 MHz, CDCl3) 7.33 (d, J=9.2 Hz, 2H), 6.98 (d, J=9.2 Hz, 2H), 6.43 (s, 1H), 4.15 (t, J=12, 6 Hz, 2H), 2.78 (t, J=12, 6 Hz, 2H), 2.53 (br, 4H), 1.61-1.47 (m, 6H); LC/MS (ESI): 94%.
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>>[OH:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[C:6]([CH3:7])=[C:2]([C:24]3[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=3)[C:18]#[N:19])[C:3]([CH3:17])=[N:4]2)=[CH:9][CH:10]=1
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Reactant: N#Cc1cccc(B(O)O)c1
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1-c1cccc(C#N)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11) and 3-cyanobenzeneboronic acid: MS (EI) m/z 317 [M]+, 1H-NMR (CDCl3) δ 7.63-7.34 (8H, m), 3.92 (2H, t, J=6.6 Hz), 2.94 (2H, t, J=6.6 Hz), 2.32 (3H, s), 2.29 (3H, s).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)(=[O:29])[CH3:28].N1C=CC=CC=1>C1COCC1>[CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:27](=[O:29])[CH3:28])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=O)NCc2ccccc2)c2c1oc1ccc(N)cc12
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCc2ccccc2)c2c1oc1ccc(NC(C)=O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-1-benzyl-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (80 mg, 0.23 mmol) (step 2) was treated with acetyl chloride (1.1 eq.) in THF (10 ml) containing pyridine (1.0 eq) at 0° C. and allowed to warm to room temperature. The reaction was stirred at room temperature for 2 h. The reaction mixture was filterd and the filterarte was concentrated. The residue was triturated with ethanol to obtain 63 mg of N1-benzyl-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid; mp: 264-265° C.
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([N+:16]([O-])=O)[N:13]=[CH:12]1)([CH3:10])[CH2:3][NH:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].[F:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]2[C:21]=1[CH2:22][CH:23]([NH:31][C@@H:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33](O)=[O:34])[CH2:24][CH2:25]2>>[F:30][C:28]1[CH:27]=[C:26]2[C:21](=[C:20]([F:19])[CH:29]=1)[CH2:22][CH:23]([NH:31][C@@H:32]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:33]([NH:16][C:14]1[N:13]=[CH:12][N:11]([C:2]([CH3:10])([CH3:1])[CH2:3][NH:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:15]=1)=[O:34])[CH2:24][CH2:25]2
Reactant: O=C(O)[C@@H](NC1CCc2cc(F)cc(F)c2C1)c1ccccc1
Reactant: CC(C)(C)CNCC(C)(C)n1cnc([N+](=O)[O-])c1
Product: CC(C)(C)CNCC(C)(C)n1cnc(NC(=O)[C@@H](NC2CCc3cc(F)cc(F)c3C2)c2ccccc2)c1

Procedure:
2-methyl-N-neopentyl-2-(4-nitro-1H-imidazol-1-yl)propan-1-amine (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was reduced and coupled with (S)-2-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-2-phenylacetic acid to afford the title compound: MS 524 m/z (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:20]1[CH2:21][CH2:22][N:17]([S:14]([CH3:13])(=[O:16])=[O:15])[CH2:18][CH2:19]1)=[N:7][N:6]=[CH:5]2
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Clc1nncc2cc(Br)ccc12
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2nncc3cc(Br)ccc23)CC1
Temperature: 120 °C

Procedure:
6-Bromo-1-chlorophthalazine (18 mg, 74 umol) and 1-(methylsulfonyl)piperazine (91 mg, 554 μmol) were dissolved in dichloromethane/methanol when the reaction mixture was concentrated by evaporation under a nitrogen line. The concentrate was heated to 120° C. for 6 h to give the title compound. MS (ES+): 373 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[I:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:36]4[CH:37]=[CH:38][C:33]([I:32])=[CH:34][CH:35]=4)(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(I)cc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-iodo-benzenesulfonyl chloride. Purity (ELSD, based on MW=687.5)=100%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH3:13])[N:10]([CH:14]3[C:18](=[O:19])/[C:17](=[CH:20]\[C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=4)/[CH2:16][C:15]3=[O:28])[N:9]=2)=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH3:13])[N:10]([CH:14]3[C:18](=[O:19])[CH:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=4)[CH2:16][C:15]3=[O:28])[N:9]=2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc(-c2ccc(Cl)cc2)nn1C1C(=O)C/C(=C/c2ccc(F)cn2)C1=O
Agent: [Pd]
Solvent: CO
Product: Cc1cc(-c2ccc(Cl)cc2)nn1C1C(=O)CC(Cc2ccc(F)cn2)C1=O
Yield: 98.7 %

Procedure:
To a solution of 2-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-4-[1-(5-fluoro-pyridin-2-yl)-meth-(Z)-ylidene]-cyclopentane-1,3-dione (17 mg, 0.04 mmol) in methanol (0.4 ml) was added 5% palladium on activated charcoal (2 mg) and the reaction stirred for 6 hours under 1.5 bar of hydrogen. The solution was then filtered through a pad of Celite, washed with methanol (10 ml) and concentrated in vacuo to give a white solid, which was purified by column chromatography using DCM:EtOAc:AcOH (9:1:0.01%) to (3:7:0.01%) to give 2-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-4-(5-fluoro-pyridin-2-ylmethyl)-cyclopentane-1,3-dione (15.7 mg).
Reaction SMILES: [K].[CH:2]([CH:4]([CH2:7][C:8]#[N:9])[C:5]#[N:6])=O.[NH2:10][CH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:9][C:8]1[N:10]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)[CH:2]=[C:4]([C:5]#[N:6])[CH:7]=1
Reactant: NC1CCc2ccccc21
Reactant: N#CCC(C#N)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc(N)n(C2CCc3ccccc32)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
Formyl succinonitrile potassium salt (36.5 g) and 1-aminoindane (36.6 g) were dissolved in water (100 ml), and acetic acid (100 ml) was added thereto. After agitating the mixture at 100° C. for 30 minutes, the reaction solution was poured into water (1200 ml). The reaction mixture was made basic by adding potassium carbonate and then extracted with ethyl acetate. After the organic layer was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure and the residue (37.4 g) was dissolved in ethanol (450 ml). After potassium ethoxide (35.2 g) was added thereto and the mixture was stirred at room temperature for 30 minutes, the reaction solution was poured into iced water (1500 ml) and extracted with ethyl acetate. After the organic layer was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography eluting with ethyl acetate-hexane (1:2, v/v) and the fractions were concentrated under reduced pressure to give 2-amino-1-(indan-1-yl)pyrrole-4-carbonitrile (20.4 g, 37%) as oily matter.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C@H:30]1[CH2:36][NH:35][C:34](=[N:37][CH2:38][CH:39](O)[CH2:40][C:41]([F:44])([F:43])[F:42])[C@H:33]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:32][CH2:31]1>C(#N)C>[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C@H:30]1[CH2:36][N:35]2[C:39]([CH2:40][C:41]([F:44])([F:43])[F:42])=[CH:38][N:37]=[C:34]2[C@H:33]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=NCC(O)CC(F)(F)F
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reaction time: 70 h
Yield: 75.3 %

Procedure:
Pyridinium dichromate (7.92 g, 21.0 mmol) was added to a solution of crude tert-butyl {(3R,6S)-6-(2,3-difluorophenyl)-2-[(4,4,4-trifluoro-2-hydroxybutyl)imino]azepan-3-yl}carbamate (3.27 g, 7.01 mmol) in acetonitrile (70 mL). After 70 h, the mixture was filtered and concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane→96% dichloromethane/methanol) gave the title compound (2.35 g). MS 446.1 (M+1). 1H NMR (500 MHz, CDCl3) δ 7.14-7.09 (m, 1H), 6.97-6.94 (m, 2H), 6.33 (d, J=5.8 Hz, 1H), 4.82 (dd, J=10.0, 3.9 Hz, 1H), 4.12-4.07 (m, 1H), 3.99 (d, J=14.6 Hz, 1H), 3.37 (q, J=20.0, 10.0 Hz, 2H), 2.94 (t, J=110.2 Hz, 1H), 2.44 (d, J=13.7 Hz, 1H), 2.34-2.26 (m, 1H), 2.16-2.13 (m, 1H), 1.63-1.60 (m, 1H), 1.57 (s, 9H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][S:20][C:21](SC)=[CH:22][N+:23]([O-:25])=[O:24].[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30]>O1CCCC1>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[N+:23]([CH:22]=[C:21]([S:20][CH3:19])[NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)([O-:25])=[O:24]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Product: CSC(=C[N+](=O)[O-])NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
A mixture of 3-[3-[(1-piperidinyl)methyl]phenoxy]propanamine (4.97 g.) and 1,1-bis-(methylthio)-2-nitroethene (6.61 g.) in tetrahydrofuran (100 ml.) was heated under reflux for 19 hours. A solution of oxalic acid (6.25%) in tetrahydrofuran (4 ml.) was added, the suspension filtered and to the filtrate was added a solution of oxalic acid (6.25%) in tetrahydrofuran (36 ml.). The solid which separated on trituration was filtered, washed with tetrahydrofuran and dried to give the title compound (7.36 g.), m.p. 71°-75°.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]([CH:16]([CH3:18])[CH3:17])[NH2:15])[CH:3]=[N:4]O.N.[H][H].O>CO.[Ni]>[CH:16]([CH:14]([NH2:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:2]([CH3:1])([CH3:19])[CH2:3][NH2:4])([CH3:18])[CH3:17]
Reactant: CC(C)C(N)CC=CCCC=CCC(C)(C)C=NO
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: O
Product: CC(C)C(N)CCCCCCCCC(C)(C)CN
Temperature: 100 °C
Reaction time: 5 h
Yield: 92.7 %

Procedure:
490 g (1.84 moles) of the 2,2-dimethyl-11-isopropyl-11-amino-undeca-4,8-dienal oxime obtained according to Example 5 are dissolved in 2.4 liters of methanol and this solution is filled, together with about 200 g of liquid ammonia, with the addition of 150 g of Raney nickel, into a 6.3 liter steel autoclave. Hydrogen is then injected until the pressure is 100 bars and the mixture is heated to 100° C. with stirring. The mixture is hydrogenated forabout 5 hours under these conditions and cooled and the ammonia and excess hydrogen are then allowed to blow off. Subsequent distillation under a high vacuum yields 436 g (1.705 mols) of 1-isopropyl-10,10-dimethyl-1,11-diaminoundecane in the form of a colourless, water-clear liquid; boiling point 87° C./4 Pa; nD20 =1.46l9.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:9][N:8]=[C:7]([Br:10])[CH:6]=1)=O.[NH2:11][C:12]([NH2:14])=[S:13]>C(O)C>[NH2:14][C:12]1[S:13][CH:2]=[C:3]([C:5]2[O:9][N:8]=[C:7]([Br:10])[CH:6]=2)[N:11]=1
Reactant: O=C(CBr)c1cc(Br)no1
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc(-c2cc(Br)no2)cs1

Procedure:
A mixture of 32.4 g (120.4 mol) of 5-bromoacetyl-3-bromoisoxazole and 18.4 g (240 mmol) of thiourea in 400 ml of anhydrous ethanol was refluxed for 90 minutes.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18].[N+](=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N-]>ClCCCl.ClC(Cl)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:17][C:12]1[C:11]2[CH:10]=[C:9]([CH3:18])[N:8]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]=2[CH:15]=[CH:14][N:13]=1)[CH3:32]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: Cc1cc2c(O)nccc2n1Cc1ccccc1-c1ccccc1
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)COc1nccc2c1cc(C)n2Cc1ccccc1-c1ccccc1

Procedure:
To a solution of intermediate (5) (0.557 g, 1.77 mmole) in 1,2-dichloroethane (250 mL) rhodium(II) trifluoroacetate dimmer (0.058 g, 0.0885 mmole) was added, the reaction was heated to reflux. Then the solution of ethyl diazoacetate (90%, 0.2 mL, 1.77 mmole) in dichloroethane (35 mL) was added via a syringe pump to the mixture over 16 h. The reaction mixture was refluxed for an additional 2 h. The solvent was evaporated and the residue was purified by column chromatography (3:1 Hex:EtOAc) to afford intermediate (6) as a yellow solid. Yield: 0.272 g, 38%.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[C:21]([Cl:23])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:17]2[CH:22]=[C:21]([Cl:23])[S:20][C:18]=2[N:19]=1
Reactant: Clc1nc(Cl)c2cc(Cl)sc2n1
Reactant: NCCc1ccc2c(c1)OCO2
Product: Clc1nc(NCCc2ccc3c(c2)OCO3)c2cc(Cl)sc2n1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 2,4,6-trichloro-thieno-[2,3-d]-pyrimidine yields 2,6-dichloro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1]/[C:2](=[N:20]\[O:21][C:22]([C@H:24]([CH2:33][CH2:34][CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=O)/[CH:3]1[CH2:6][N:5]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4]1>C1(C)C=CC=CC=1>[CH:7]([N:5]1[CH2:6][CH:3]([C:2]2[N:1]=[C:22]([C@H:24]([CH2:33][CH2:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:25][C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[O:21][N:20]=2)[CH2:4]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O/N=C(\N)C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C2CN(C(c3ccccc3)c3ccccc3)C2)no1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A solution of tert-butyl(3R)-3-[({[(Z)-amino(1-benzhydryl-3-azetidinyl)methylidene]amino}oxy)carbonyl]-6-cyclohexylhexanoate (preparation 35) (2.85 g, 5.07 mmol) in toluene (90 ml) was heated at 140° C. under Dean and Stark conditions for 18 hours. The reaction mixture was allowed to cool to room temperature. The solvent was removed under reduced pressure. The residue was purified on a silica column eluting with a solvent gradient of cyclohexane:Et2O (90:10) gradually changing to (60:40) to afford the title compound as a colourless oil (2.0 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:18])=[C:6]([CH:17]=1)[C:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=[O:8].[Cl:20][C:21]1[CH:22]=[C:23]([OH:30])[CH:24]=[N:25][C:26]=1[CH:27]1[CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:30][C:23]2[CH:24]=[N:25][C:26]([CH:27]3[CH2:29][CH2:28]3)=[C:21]([Cl:20])[CH:22]=2)=[CH:4][C:5]([F:18])=[C:6]([CH:17]=1)[C:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=[O:8]
Reactant: Cc1ccc(OC(=O)c2cc(Cl)c(F)cc2F)cc1
Reactant: Oc1cnc(C2CC2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3cnc(C4CC4)c(Cl)c3)cc2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.2 %

Procedure:
4-Methylphenyl 5-chloro-2,4-difluorobenzoate (Preparation 26, 0.330 g, 1.168 mmol) was added portionwise over 5 minutes to a suspension of 5-chloro-6-cyclopropylpyridin-3-ol (Preparation 69, 0.214 g, 1.262 mmol) and potassium carbonate (0.32 g, 2.315 mmol) in DMSO (5.0 mL). The mixture was stirred at room temperature for 3 hours, then partitioned between water (20.0 mL) and tert-butyl methyl ether (20.0 mL). The organic layer was further washed with water (2×20.0 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified with silica gel chromatography eluting with 0 to 5% EtOAc in heptane to yield the title compound as a white solid (0.289 g, 0.668 mmol, 57%):
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:38])([CH3:37])[CH2:9][C:10]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[CH:7]=1.[NH2:41][C@@H:42]([C:45]([OH:47])=[O:46])[CH2:43][OH:44]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:37])([CH3:38])[CH2:9][C:10]([OH:36])([C:32]([F:34])([F:35])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([C:26]([NH:41][C@@H:42]([C:45]([OH:47])=[O:46])[CH2:43][OH:44])=[O:27])[CH:29]=[CH:30][CH:31]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Reactant: N[C@H](CO)C(=O)O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N[C@H](CO)C(=O)O)c1)C(F)(F)F

Procedure:
Prepared similarly to Intermediate 4 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and D-serine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Br:10])[CH:9]=1)(=[NH:3])[NH2:2].CO[CH:13](OC)[CH2:14][CH:15](OC)OC>CN(C=O)C>[Br:10][C:8]1[CH:7]=[N:6][CH:5]=[C:4]([C:1]2[N:2]=[CH:15][CH:14]=[CH:13][N:3]=2)[CH:9]=1
Reactant: N=C(N)c1cncc(Br)c1
Reactant: COC(CC(OC)OC)OC
Solvent: CN(C)C=O
Product: Brc1cncc(-c2ncccn2)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 21.7 %

Procedure:
A mixture of the product of Step B (4.86 g, 20.5 mmol) and 1,1,3,3-tetramethoxypropane (6.59 mL, 40 mmol) in DMF (25 mL) was warmed to 90° C. under N2. After 18 h, the reaction mixture was allowed to cool to 25° C., concentrated in vacuo. Purification of the residue by flash chromatography (EtOAc) afforded the title compound (1.05 g, 22%) as a white solid. MS 237 (M+H)+