Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[C:8]([N+:18]([O-])=O)=[CH:9][CH:10]=[C:11]4[C:17]=3[C@H:14]([CH2:15]2)[CH2:13][NH:12]4)[CH2:5][C@H:4]([NH:21][C:22](=[O:28])[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:3]1.[BH4-].[Na+].Cl.N>CO.[Ni](Cl)Cl>[NH2:18][C:8]1[C:7]2=[C:17]3[C:11]([NH:12][CH2:13][CH:14]3[CH2:15][C@@H:16]3[C@@H:6]2[CH2:5][C@H:4]([NH:21][C:22](=[O:28])[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:3][N:2]3[CH3:1])=[CH:10][CH:9]=1
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c([N+](=O)[O-])ccc4c3[C@@H](CN4)C[C@H]2N(C)C1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: N
Solvent: CO
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(N)ccc4c3C(CN4)C[C@H]2N(C)C1
Yield: 97.9 %

Procedure:
One millimole of 3-(2,3β-dihydro-6-methyl-12-nitro-8α-ergolinyl)-1,1-diethylurea is dissolved in 25 ml of methanol, cooled in an ice bath, and 2 mmol of nickel chloride (with 6H2O) and thereafter 5 mmol of sodium borohydride are added thereto in 4-5 portions. Under ice cooling, the mixture is acidified with 2N hydrochloric acid, combined with dilute ammonia solution, and extracted by shaking. After drying and evaporation of the organic phase, 350 mg of 3-(12-amino-2,3-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea is obtained. [α]D =-31° (0.5% methanol) as the tartaric acid salt (1:1).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][CH:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]3)=[CH:19][CH:18]=2)[CH:14]=[C:15]1[C:20]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCOCC2)n3Cc2ccccc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 1, the title compound was synthesized from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone (intermediate 2) and benzyl bromide. The title compound was obtained in 4% yield as white solid. MS (m/e): 462.2 (MH+, 100%).
Reaction SMILES: N1C=CNC(=O)C1=O.ClC1C(Cl)=NC=CN=1.NN.[Cl:19][C:20]1[C:25]([NH:26][NH2:27])=[N:24][CH:23]=[CH:22][N:21]=1.F[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36](OCC)(OCC)OCC>C1(C)C(C)=CC=CC=1>[Cl:19][C:20]1[C:25]([NH:26][NH2:27])=[N:24][CH:23]=[CH:22][N:21]=1.[CH2:35]([C:36]1[N:24]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:19])[C:25]2=[N:26][N:27]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:29]=1
Reactant: CCOC(Cc1ccccc1F)(OCC)OCC
Agent: Clc1nccnc1Cl
Agent: NN
Agent: NNc1nccnc1Cl
Solvent: Cc1ccccc1C
Product: Clc1nccn2c(Cc3ccccc3)nnc12
Yield: 96 %

Procedure:
2-Chloro-3-hydrazinopyrazine was prepared in four steps. The procedure of J. Adachi and N. Sato, J.Org.Chem. 37, 221 (1972) was used to prepare 2,3(1H,4H)-pyrazinedione in two steps, followed by chlorination and reaction of the dichloropyrazine with hydrazine as described in S. W. Schneller and J. L. May, J.Het.Chem. 15,987 (1978). A mixture of 2-chloro-3-hydrazinopyrazine (8.51 g, 58.9 mmol), 1-fluoro-2-(2,2,2-triethoxyethyl)benzene from 1(A) (34.7 g, 135 mmol) and xylene (125 mL) (dried over calcium chloride) was refluxed for 3 hours. The solvent was removed by spin evaporation in vacuo. The solid residue was triturated in ether (200 mL) and the solid was collected by suction filtration. The solid was rinsed with ether and dried with aspirator suction to give 14.9 g (96%) of crude 3-benzyl-8-chloro-1,2,4-triazolo[4,3-a]pyrazine. Recrystallisation of 1.0 g of crude 3-benzyl-8-chloro-1,2,4-triazolo[4,3-a]pyrazine from ethanol:water gave 0.697 g of the analytically pure product, mp. 126°-127° C.; UV (0.1 N hydrochloride acid+10% ethanol): λmax 300 nm (ε4200); (pH 7.0 buffer+10% ethanol): λmax 300 nm (ε4300); nmr(DMSO-d6) δ8.58 (d, 1H, J=4.7 Hz, H-5 or H-6), 7.79 (d, 1H, J=4.7 Hz, H-5 or H-6), 7.09-7.40 (complex multiplets, 4H, ArH), 4.60 (s, 2H, CH2); ms: m/e 262 (M+), 261 (M-1+), 243 (M-F+), 227 (M-Cl+), 109 (C7H6F+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([O:33][CH3:34])[CH:16]=[C:17]([C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:32])[CH:24]=4)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:36]1C=C(S(Cl)(=O)=O)C=C[CH:41]=1>>[CH2:36]([O:28][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][C:23]([NH:22][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:9])=[C:15]([O:33][CH3:34])[CH:16]=2)=[O:21])=[CH:24][C:25]=1[F:32])[CH3:41]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)c(F)c2)cc2c1CCN2S(=O)(=O)c1cccc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CC3)cc1F

Procedure:
4-{[1-(3-Chloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 505.29 (M+H+.), was prepared in analogy to example 14, steps 1 to 6. Step 5 was performed using 3-chloro-benzenesulfonyl chloride and yielded 4-{[1-(3-chloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:36][CH:33]3[CH2:35][CH2:34]3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCOCC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC1CC1)N1CCN(C2CCCC2)CC1
Yield: 38 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4-cyclopentyl-piperazin-1-yl)-[2-(morpholine-4-carbonyl)-1H-indol-5-yl]-methanone (example 10), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless foam (38%).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][CH3:5])[CH3:2].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:44][NH:45][S:46]([CH2:49][C@@H:50]([NH2:55])[CH2:51][CH:52]([CH3:54])[CH3:53])(=[O:48])=[O:47].Cl>CN(C=O)C.O.C(Cl)CCl>[CH3:53][CH:52]([CH3:54])[CH2:51][C@H:50]([NH:55][C:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]([CH2:18][C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[N:8][C:9]=2[CH:14]=1)=[O:17])[CH2:49][S:46](=[O:48])(=[O:47])[NH:45][CH3:44]
Reactant: CNS(=O)(=O)C[C@@H](N)CC(C)C
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@@H](CC(C)C)CS(=O)(=O)NC)ccc21
Reaction time: 20 h

Procedure:
To a solution of 80 mg of 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid in 0.5 ml of dry DMF 17 mg of HOAT, 56 mg of EDC and 0.24 ml of DIPEA were added at 0° C. After 15 min 60 mg of (S)-2-Amino-4-methyl-pentane-1-sulfonic acid methylamide-hydrochloride were added and the reaction was stirred at it for 20 h. The reaction was then poured into water and the pH was adjusted to 3 by the addition of 2 M aqueous hydrochloric acid. The reaction was extracted with ethyl acetate three times. The combined organic phases were washed with 2 M aqueous hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated. After purification by HPLC 55 mg (45%) of 1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid ((S)-3-methyl-1-methylsulfamoylmethyl-butyl)-amide were obtained.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH2:18]([C:20]1[C:21]([CH:34]=O)=[CH:22][C:23]2[C:24]([CH3:33])([CH3:32])[CH2:25][CH2:26][C:27]([CH3:31])([CH3:30])[C:28]=2[CH:29]=1)[CH3:19]>>[CH2:18]([C:20]1[C:21]([C:34]#[C:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[CH:7][CH:8]=2)=[CH:22][C:23]2[C:24]([CH3:33])([CH3:32])[CH2:25][CH2:26][C:27]([CH3:31])([CH3:30])[C:28]=2[CH:29]=1)[CH3:19]
Reactant: CCc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc(C)cc1
Product: CCc1cc2c(cc1C#Cc1ccc(C)cc1)C(C)(C)CCC2(C)C
Yield: 25.1 %

Procedure:
Using a process similar to that described in Example 13, 27.7 g (0.1 mole) of diethyl 1-chloro-1-(4-tolyl)-methylphosphonate, 24.4 g (0.1 mole) of 3-ethyl-2-formyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene and 22.5 g (0.2 mole) of potassium tert.-butylate were reacted for 1 hour to give 8.3 g (25%) of the title compound of melting point 72°-73° C., the reaction mixture being poured onto water and acidified, and the precipitate which had separated out being recrystallized from methanol and once again from isopropanol.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[N:10]([C:18]3[CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[S:21][CH:22]=3)[N:11]=[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:3]=12.C(OCC)(=O)C.O.C[C:35]([N:37](C)C)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[C:35]([C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[N:10]([C:18]3[CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[S:21][CH:22]=3)[N:11]=[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:3]=12)#[N:37]
Reactant: CC(=O)N(C)C
Reactant: COC(=O)c1cc(-n2nc(C3CCCC3)c3c(Br)cnc(OC)c32)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(-n2nc(C3CCCC3)c3c(C#N)cnc(OC)c32)cs1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A suspension of methyl 4-(4-bromo-3-cyclopentyl-7-methoxy-1H-pyrazolo[3,4-c]pyridin-1-yl)thiophene-2-carboxylate (65 mg), tetrakis(triphenylphosphine)palladium(0) (34.4 mg) and zinc cyanide (26.2 mg) in DMA (3 mL) was stirred under microwave irradiation at 120° C. for 30 min. To the reaction mixture were added ethyl acetate and water, and the mixture was filtered through Celite. The filtrate was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (40 mg).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.BrC[CH2:16][C:17]#[N:18]>>[N:8]1([CH2:6][CH2:16][C:17]#[N:18])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: N#CCCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: N#CCCN1CCNCC1

Procedure:
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine and 3-bromopropionitrile in an analogous manner as described in example 21.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([CH3:9])[CH:3]=1.C(N(CC)CC)C.Cl.Cl[CH2:19][C:20]1[N:24]([CH2:25][CH2:26][CH3:27])[CH:23]=[N:22][C:21]=1[CH3:28].O>O1CCCC1.CO>[CH3:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[S:8][CH2:19][C:20]1[N:24]([CH2:25][CH2:26][CH3:27])[CH:23]=[N:22][C:21]=1[CH3:28])[NH2:1]
Reactant: CCCn1cnc(C)c1CCl
Reactant: Cc1cc(N)ccc1S
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCn1cnc(C)c1CSc1ccc(N)cc1C
Reaction time: 3 h
Yield: 30.4 %

Procedure:
To a solution of 4-amino-2-methylthiophenol (500 mg) and triethylamine (3.0 ml) in tetrahydrofuran (15 ml) was added dropwise a solution of 5-chloromethyl-4-methyl-1-propylimidazole hydrochloride (908 mg) in methanol (5 ml) at 0° C. under argon atmosphere, after which the mixture was returned to room temperature and stirred for 3 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate) to give 3-methyl-4-[((4-methyl-1-propylimidazol-5-yl)methyl)sulfanyl]aniline (301 mg) as a brown powder.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[F:21][C:22]([F:45])([F:44])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])(=[O:31])=[O:30].Cl.CN(C)CCCN=C=NCC.Cl.Cl.[N:60]1([CH2:65][CH2:66][O:67][C:68]2([C:74]3[CH:75]=[N:76][CH:77]=[CH:78][CH:79]=3)[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]2)[CH2:64][CH2:63][CH2:62][CH2:61]1>C(Cl)Cl>[N:76]1[CH:77]=[CH:78][CH:79]=[C:74]([C:68]2([O:67][CH2:66][CH2:65][N:60]3[CH2:64][CH2:63][CH2:62][CH2:61]3)[CH2:73][CH2:72][N:71]([C:41](=[O:42])[CH2:40][CH2:39][CH2:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][N:32]3[S:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22]([F:21])([F:45])[F:44])(=[O:30])=[O:31])[CH2:70][CH2:69]2)[CH:75]=1
Reactant: c1cncc(C2(OCCN3CCCC3)CCNCC2)c1
Reactant: O=C(O)CCCC1CCCCN1S(=O)(=O)c1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCC1CCCCN1S(=O)(=O)c1ccccc1C(F)(F)F)N1CCC(OCCN2CCCC2)(c2cccnc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1-Hydroxybenzotriazole hydrate (HOBT) (0.021 g, 0.158 mmol, 0.3 eq.) and N-ethyl-diisopropylamine (0.269 ml, 1.59 mmol, 3 eq.) were added to a solution of 4-(1-(2-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)butanoic acid (0.251 g, 0.66 mmol, 1.25 eq.) in methylene chloride (7 ml). The mixture was cooled to 0° C., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (0.152 g, 0.792 mmol, 1.5 eq.) was added and the mixture was stirred for approx. 15 min. 3-(4-(2-(Pyrrolidin-1-yl)ethoxy)piperidin-4-yl)pyridine dihydrochloride (0.184 g, 0.528 mmol, 1 eq.) was then added. The reaction mixture was stirred at room temperature for 72 h.
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[NH2:7][C:8]1[C:9]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])=O)=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2.[BH4-].[Na+]>N1C=CC=CC=1>[CH3:29][O:28][C:21]1[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=1[CH:18]1[C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[N:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[NH:7][S:3](=[O:5])(=[O:4])[N:2]1[CH3:1]
Reactant: COc1ccc(C(=O)c2ccc3cccnc3c2N)c(OC)c1
Reactant: CNS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C2c3ccc4cccnc4c3NS(=O)(=O)N2C)c(OC)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 16 %

Procedure:
N-methylsulfamyl chloride (Intermediate 213) (504 mg, 3.88 mmol) was added dropwise to a solution of (8-amino-quinolin-7-yl)-(2,4-dimethoxy-phenyl)-methanone (Intermediate 379) (200 mg, 0.65 mmol) in dry pyridine (10 ml) at 0° C. and the mixture was stirred at room temperature for 36 h (additional equivalents of methylsulfamyl choride were added as required after 24 h). After completion of the reaction (monitored by LCMS), NaBH4 (95 mg, 2.58 mmol) was added and reaction was stirred at room temperature for 18 h. The reaction was quenched with water, concentrated in vacuo and the residue was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (99:1) as the eluent to give the title compound (40 mg, 16%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[ClH:14]>C1C=CC=CC=1.[Cl-].[Cd+2].[Cl-]>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:2]1[CH:10]=[CH:9][C:8]([Cl:14])=[CH:7][CH:3]=1)=[O:5]
Reactant: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Reactant: Cl
Agent: [Cd+2]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cc1c(C(=O)c2ccc(Cl)cc2)cccc1[N+](=O)[O-]
Temperature: 8 °C
Reaction time: 18 h

Procedure:
A mixture of 30 g of magnesium and 450 ml of ether was refluxed and then a solution of 191 g of p-chlorobromobenzene in 600 ml of ether was slowly added and reflux was continued for 11/2 hours after the addition. The mixture was cooled to 20° C to obtain an ether solution of 0.7N p-chlorophenyl magnesium bromide. After cooling 800 ml of the solution to 10° C, 55.7 g of cadmium chloride were added thereto and the ether was distilled off while adding benzene as a replacement. After obtaining 1 1 of distillate, it was cooled to 8° C and a solution of 110 g of 2-methyl-3-nitro-benzoyl chloride in 550 ml of benzene was added thereto. The mixture stood for 18 hours and was then added to a mixture of 3,650 ml of icewater and 134 ml of hydrochloric acid. The mixture was filtered and the benzene phase was decanted. The aqueous phase was extracted with benzene and the combined benzene phases were washed with N hydrochloric acid, with water, with saturated aqueous sodium bicarbonate and finally with water. The organic phase was dried over sodium sulfate and evaporated to dryness under reduced pressure to obtain 147.3 g of 2-methyl-3-nitro-4'-chloro-benzophenone which was used as is in the next step.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[NH:49][CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]2[C:34]=1[C:33]([CH3:36])([CH3:35])[CH2:32][CH2:31]2.[C:52]([O:56][C:57](=[O:66])[CH2:58][C@H:59]1[CH2:62][C@H:61]([C:63](O)=[O:64])[CH2:60]1)([CH3:55])([CH3:54])[CH3:53].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[N:49]([C:63]([C@H:61]3[CH2:60][C@H:59]([CH2:58][C:57]([O:56][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:66])[CH2:62]3)=[O:64])[CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]2[C:34]=1[C:33]([CH3:35])([CH3:36])[CH2:32][CH2:31]2
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@H](C(=O)O)C1
Reactant: COc1ccc2c(n1)CCN[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (113 mg, 0.30 mmol) was added to a solution of (R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide (100 mg, 0.27 mmol), trans-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (63.8 mg, 0.30 mmol) and DIEA (0.053 mL, 0.30 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give tert-butyl 2-(trans-3-((R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclobutyl)acetate (150 mg, 0.27 mmol, 98%) as a colorless oil.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9]=[N:10][NH:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20].[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ClOC(C)(C)C.[F:36][P-:37]([F:42])([F:41])([F:40])([F:39])[F:38].[K+]>ClCCl>[F:36][P-:37]([F:42])([F:41])([F:40])([F:39])[F:38].[CH3:21][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH+:9]1[CH:29]=[C:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:11]([C:12]2[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=2[CH3:18])[NH:10]1
Reactant: Cc1cc(C)c(N=NNc2c(C)cc(C)cc2C)c(C)c1
Reactant: C#Cc1ccccc1
Agent: CC(C)(C)OCl
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(C)c(N2N[NH+](c3c(C)cc(C)cc3C)C=C2c2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of triazene 8b (845 mg, 3 mmol) and phenylacetylene 9a (660 μL, 6 mmol) in dry dichloromethane (20 mL) in the dark at −78° C. is added tert-butyl hypochlorite (500 μL, 4.4 mmol), upon which the mixture instantly darkens. The mixture is stirred overnight as it is slowly allowed to warm to room temperature. The contents are then filtered, and the solid residue is washed with dichloromethane. The filtrate is collected, and volatiles are evaporated under reduced pressure. The crude solid is redissolved in acetone (20 mL), to which is then added potassium hexafluorophosphate (750 mg, 4 mmol). The mixture is stirred at room temperature for ca. 1 hour, filtered, and the solid residue is washed with dichloromethane. The collected filtrate is evaporated under reduced pressure. Diethyl ether is then added, and the mixture is vigorously triturated for ca. 1 hour, with occasional scratching of the glass surfaces to ensure efficient mixing. Filtration and washing with copious quantities of diethyl ether afford, after drying under vacuum, triazolium salt 10ba as an off-white solid (1.42 g, 89%). Analytical samples were obtained after recrystallization by vapor diffusion of diethyl ether in an acetonitrile solution of 10ba. 1H-NMR (CD3CN, 300 MHz): δ=9.03 (s, 1H), 7.61 (tt, J=7.2, 1.5 Hz, 1H), 7.53-7.43 (m, 4H), 7.24 (s, 2H), 7.20 (s, 2H), 2.42 (s, 3H), 2.39 (s, 3H), 2.21 (s, 6H), 2.04 (s, 6H). 13C-NMR (CD3CN, 75 MHz): δ=145.9, 144.7, 144.4, 136.0, 135.6, 133.5, 132.5, 131.3, 131.0, 130.8, 129.5, 122.9, 21.4, 17.7, 17.6. HR-MS (ESI): Calcd. for C26H28N3 [M+]: 382.2278. found 382.2288.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[C:6]([CH:28]([CH3:30])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[C:6]([CH:28]([CH3:30])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccccc1/C=C/c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccccc1CCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6diisopropyl-3-hydroxymethyl-(4-fluorophenyl)-5-[2(E)-(2-methylphenyl)ethenyl]pyridine (Example 40) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.16 (m, 4 H), 7.06 (m, 3 H), 6.81 (m, 1 H), 4.35 (d, J=4 Hz, 2 H), 3.42 (sept, J=6.6 Hz, 2 H), 2.57 (m, 4 H), 1.97 (s, 3 H), 1.36 (d, J=6.6 Hz, 6 H), 1.35 (d, J=6.6 Hz, 6 H), 1.19 (m, 1 H). FAB-MS: calculated for (C27H32FNO) 405, found 406 (M+H). Anal. Calcd for C27H32FNO: C, 79.96; H, 7.95; N, 3.45. Found: C, 80.08; H, 8.05; N, 3.46. mp 125-126° C. Rf=0.3 (20% ethyl acetate/hexane).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](OBr)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[K+].CC(C)CC(O)C>>[CH2:21]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCCCCCOBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)CC(C)O
Product: CCCCCCCCCCCCOc1ccc(C=O)cc1
Yield: 77.4 %

Procedure:
100 g of 4-hydroxy-benzaldehyde are reacted with 224.5 g of dodecyloxybromide along with 56.7 g of anhydrous KOH (85%) in 11 of 4-methyl-2-hydroxy-pentane. The mixture is then heated to reflux and maintained at reflux for 7 hours. The cooled reaction mixture is filtered to eliminate salts and distilled in a claisen equipment. 184 g (yield 77%) of a clear oil are collected at 178-181° C. and 0.5 mbar, which slowly crystallises on standing at room temperature.