Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:33][CH3:34])[C:31]=1[CH3:32])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:12][C:11]=1[NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])=[O:7].CI.[C:37](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:33][CH3:34])[C:31]=1[CH3:32])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:12][C:11]=1[N:22]([CH3:37])[C:23](=[O:28])[C:24]([F:26])([F:25])[F:27])=[O:7]
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NC(=O)C(F)(F)F)cc(OC)c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N(C)C(=O)C(F)(F)F)cc(OC)c1C
Temperature: 50 °C
Yield: 97.1 %

Procedure:
A suspension of compound 1h (1.1 g, 2.3 mmol), methyl iodide (0.72 mL, 11.5 mmol) and potassium carbonate (1.6 g, 11.5 mmol) in acetone (14 mL) was sealed in a pressure tube and heated at 50° C. for 3 h. The reaction mixture was cooled to rt, filtered, and concentrated on a rotary evaporator to give compound 1i (1.1 g, 100%) as a light yellow solid. ESI-MS m/e 493.1 (M+1).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[AlH4-].[Li+]>CCOCC>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [AlH4-]
Agent: [Li+]
Solvent: CCOCC
Product: OC1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1,4-Dioxa-spiro[4.5]decan-8-one (2.00 g, 0.0128 mol) was dissolved in ether (50 mL) and the mixture was cooled to 0° C. To the reaction was added 1 M lithium tetrahydroaluminate in ether (7.0 mL) and this mixture was stirred at 0° C. for 2 hours at which time TLC analysis showed no starting material present. The reaction was then quenched with water and 1 N NaOH (0.5 mL of each) and then filtered. The filtered solid was washed with ether and the combined ether filtrate was concentrated using a rotary evaporator to give the product. NMR (CDCl3): 3.94 (m, 4H), 3.81 (m, 1H), 1.79-1.92 (m, 4H), 1.54-1.70 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15](=[O:18])(=[O:17])[NH2:16])=O)[CH3:2]>P(Cl)(Cl)(Cl)=O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15](=[O:18])(=[O:17])[N:16]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)Nc1ccccc1S(N)(=O)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CC1=NS(=O)(=O)c2ccccc2N1
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 12 (2.50 g, 8.73 mmol) in phosphorous oxychloride (50 mL) was heated under reflux for 6 h, cooled to room temperature, and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and extracted with saturated Na2CO3 (100 mL). The organic layer was washed with 1 N HCl (50 mL), dried over MgSO4, and concentrated in vacuo to give 4c (1.99 g, 85%) as a yellow solid. 1H NMR (400 MHz, D6-DMSO) δ 12.22 (s, 1H), 7.79 (d, J=12 Hz, 1 H), 7.67 (t, J=10 Hz, 1 H), 7.45 (t, J=8 Hz, 1 H), 7.30 (d, J=8 Hz, 1 H), 4.15 (dt, J=7.2, 7.2 Hz, 2H), 3.69 (s, 2 H), 1.21 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [CH3:1][C:2]1([OH:15])[CH2:5][N:4]([C:6]2[CH:7]=[N:8][C:9]([N+:12]([O-])=O)=[CH:10][CH:11]=2)[CH2:3]1>[Pd].CO>[NH2:12][C:9]1[N:8]=[CH:7][C:6]([N:4]2[CH2:5][C:2]([CH3:1])([OH:15])[CH2:3]2)=[CH:11][CH:10]=1
Reactant: CC1(O)CN(c2ccc([N+](=O)[O-])nc2)C1
Agent: [Pd]
Solvent: CO
Product: CC1(O)CN(c2ccc(N)nc2)C1
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A 100-mL Parr hydrogenation bottle was purged with nitrogen and charged with 207a (2.3 g, 11 mmol), 10% palladium on carbon (50% wet, 1.0 g) and methanol (100 mL). The bottle was evacuated, charged with hydrogen gas to a pressure of 25 psi and shaken for 2 h on a Parr hydrogenation apparatus. The hydrogen was then evacuated and nitrogen charged to the bottle. The catalyst was removed by filtration through a pad of Celite and the filtrate was concentrated under reduced pressure to afford 207b (1.85 g, 92%). MS: [M+H]+ 180.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][NH:25][CH2:26]3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1>O1CCCC1>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][N:25]([C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=4)=[O:11])[CH2:26]3)=[CH:21][CH:20]=2)=[CH:17][CH:18]=1
Reactant: O=C=Nc1ccc(CCl)cc1
Reactant: Cc1ccc(-c2ccc3c(c2)CNCC3)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)CN(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A solution of 4-(chloromethyl)phenylisocyanate (0.38 g) in tetrahydrofuran was added dropwise under ice cooling into a solution of 7-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinoline (0.5 g) in tetrahydrofuran. The resulting mixture was stirred for one hour and was then evaporated to remove the solvent to obtain 4-(7-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-2-ylcarbonylamino)benzyl chloride (0.82 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH2:18][CH3:19])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[Cl:21][C:22]1[C:23]([CH:30]=O)=[N:24][N:25]([CH:27]([F:29])[F:28])[CH:26]=1>>[Cl:21][C:22]1[C:23]([CH2:30][NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]3([CH2:18][CH3:19])[C:14]([F:15])([F:16])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]3)[CH:7]=2)=[N:24][N:25]([CH:27]([F:29])[F:28])[CH:26]=1
Reactant: O=Cc1nn(C(F)F)cc1Cl
Reactant: CC[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Product: CC[C@]1(c2cc(NCc3nn(C(F)F)cc3Cl)ccc2F)N=C(N)COCC1(F)F
Yield: 23.2 %

Procedure:
In an analogous manner as described for example 2 the reductive amination of (R)-5-(5-amino-2-fluoro-phenyl)-5-ethyl-6,6-difluoro-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine (intermediate A10F) (28.7 mg, 100 μmol) and 4-chloro-1-difluoromethyl-1H-pyrazole-3-carbaldehyde (19.9 mg, 110 μmol) yielded the title compound (10.5 mg, 23.2%) as a colorless oil. MS (ISP): m/z=452.1 [M+H]+and 454.1 [(M+2+H)+].
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:10][OH:11]>F[P-](F)(F)(F)(F)F.C([N+](CCC)(CCC)CCC)CC>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:11][CH3:10])(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)N1CCCCC1
Agent: CCC[N+](CCC)(CCC)CCC
Agent: F[P-](F)(F)(F)(F)F
Product: COC1CCCCN1C(C)=O
Yield: 80.5 %

Procedure:
In the same manner as indicated in Example 6 there are electrolyzed 21.6 g of N-acetylpiperidine and 54.4 g of methanol in the presence of 0.56 g of tetra-n-propylammonium hexafluorophosphate as conducting salt. After throughput of 2.0 Faraday per mol of N-acetylpiperidine the current is switched off. The calculated mean cell voltage is 28.7 volts. Work-up of the electrolysis solution by molecular distillation gives 21.5 g of 1-acetyl-2-methoxypiperidine, which corresponds to a product yield of 80.5% and a current efficiency of 80.5%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[NH:15][CH2:16][CH2:17][CH2:18][N:19]=1)C.COC1C=CC=CC=1OCCCNCCCNC1NCCCN=1.O1C2C=CC=C(OCCNCCCNC3N=CC=CN=3)C=2OCC1.O1C2C=CC=C(OCCNCCCNC3NCCCN=3)C=2OCC1>>[CH3:1][O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[NH:19][CH2:18][CH2:17][CH2:16][N:15]=1
Reactant: CCOc1ccccc1OCCNCCCNC1=NCCCN1
Agent: COc1ccccc1OCCCNCCCNC1=NCCCN1
Agent: c1cc(OCCNCCCNC2=NCCCN2)c2c(c1)OCCO2
Agent: c1cnc(NCCCNCCOc2cccc3c2OCCO3)nc1
Product: COc1ccccc1OCCNCCCNC1=NCCCN1

Procedure:
N-[2-(2-ethoxyphenoxy)ethyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine; N-[3-(2-methoxyphenoxy)propyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine; N-[2-[(2,3-dihydro-1,4-benzodioxin-5-yl)oxy]ethyl]-N'-2-pyrimidinyl-1,3-propanediamine; N-[2-[(2,3-dihydro-1,4-benzodioxin-5-yl)oxy]ethyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[N:16]=O.[CH:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=O.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)(Cl)Cl>[N:20]1([C:18]2[NH:16][C:3]3[C:4](=[O:15])[N:5]([CH2:12][CH2:13][CH3:14])[C:6](=[O:11])[N:7]([CH2:8][CH2:9][CH3:10])[C:2]=3[N:1]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CCCn1c(N)c(N=O)c(=O)n(CCC)c1=O
Reactant: O=CN1CCOCC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCn1c(=O)c2[nH]c(N3CCOCC3)nc2n(CCC)c1=O
Reaction time: 12 h

Procedure:
7.9 g (0.033 mol) of 6-amino-5-nitroso-1,3-dipropyluracil and 5.0 g (0.049 mol) of N-formylmorpholine are dissolved in 40 ml of carbon tetrachloride. At ambient temperature, 7.5 g (0.049 mol) of phosphorus oxychloride are added, the mixture is heated to reflux temperature for one hour and left to stand at ambient temperature for about 12 hours. The oil which separates off on the surface is removed, dissolved in 50 ml of dichloromethane and poured onto ice together with the remaining solution, which has been concentrated by half. After neutralisation of the aqueous phase the organic phase is separated off and the aqueous phase is extracted with dichloromethane. From the combined organic phases the title compound is obtained, after drying and evaporation, as a crystalline residue which is recrystallised from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:26]4[CH:27]=[CH:28][C:23]([NH2:22])=[N:24][CH:25]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: Nc1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)cn1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (73 mg, 0.25 mmol) and 2-amino-5-bromopyridine (43 mg, 0.25 mmol) according to general procedure II. Obtained as an orange solid (14 mg, 15%). MS (ISP) 386.3 [(M+H)+]; mp 233–235° C.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH3:14])[C:2]#[CH:3].[OH2:15].[K+].[Br-]>N1C=CC=CC=1CO.CC([O-])=O.CC([O-])=O.[Cu+2].O>[CH3:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[NH:4][CH2:1][C:2]#[C:3][C:3]#[C:2][CH2:1][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:12])=[O:15])=[CH:7][C:6]=1[CH3:14]
Reactant: C#CCNc1ccc([N+](=O)[O-])cc1C
Reactant: O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OCc1ccccn1
Product: Cc1cc([N+](=O)[O-])ccc1NCC#CC#CCNc1ccc([N+](=O)[O-])cc1C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a suspension of Cu(OAc)2.H2O (1.5 g) in pyridinemethanol (1:1, 15 ml) was added N-(2-propynyl)-2-methyl-4-nitroaniline (1.00 g, 5.26×10-3 mole). The reaction mixture was stirred at 50° C. for two hours. The mixture was poured into excess water and filtered. The crude solid was recrystallized from nitromethane to afford yellow crystals. Yield: 0.70 g (71%). The material did not melt below 200° C. but turned red at 150° C. I.R. (KBr): 3390 (NH), 1585 and 1280 cm-1 (Ar-NO2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([C:23](O)=O)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1(OP(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=CC=1>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]2[N:9]=[C:23]([C@@H:19]3[CH2:20][CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:16])[CH2:18]3)[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: Cc1cccc(N)c1N
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Product: Cc1cccc2[nH]c([C@@H]3CCCN(C(=O)OC(C)(C)C)C3)nc12
Yield: 20.6 %

Procedure:
Into a microwave vial was added 3-methylbenzene-1,2-diamine (150 mg, 1.23 mmol) and (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (281 mg, 1.23 mmol). The mixture was dissolved with pyridine (6.2 mL). Triphenylphosphite (469 mg, 1.51 mmol) was added and the vial was capped. The reaction was microwaved at 220° C. for 10 minutes. Solvent was removed under vacuum and the residue was purified by preparatory LC/MS (20-30% CH3CN in H2O) to give (R)-tert-butyl 3-(4-methyl-1H-benzo[d]imidazol-2-yl)piperidine-1-carb oxylate (39A) (80 mg, 21% yield). ESI-MS:m/z 316.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2([OH:12])[CH2:11][CH2:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[F:15][C:16]([F:20])([F:19])[CH2:17][OH:18]>>[OH:12][C:8]1([C:7]2[C:2]([O:18][CH2:17][C:16]([F:20])([F:19])[F:15])=[CH:3][C:4]([C:13]#[N:14])=[N:5][CH:6]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: N#Cc1cc(Cl)c(C2(O)CCC2)cn1
Reactant: OCC(F)(F)F
Product: N#Cc1cc(OCC(F)(F)F)c(C2(O)CCC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 123c, using 4-chloro-5-(1-hydroxycyclobutyl)pyridine-2-carbonitrile (Example 126b) and 2,2,2-Trifluoro-ethanol (CAN 75-89-8) as starting material and isolated (609 mg, 71%); MS (ESI, m/z): 273.4 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: C#CCCc1nc2ccccc2s1
Reactant: Brc1ccccn1
Product: C(#Cc1ccccn1)CCc1nc2ccccc2s1
Yield: 45 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (127 mg, 0.80 mmol) and 2-(but-3-ynyl)benzo[d]thiazole (150 mg, 0.80 mmol). Reaction time: 1 day. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 96 mg (0.36 mmol, 45%) of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as an orange solid (M.P.=98.5-99.4° C.).
Reaction SMILES: [NH:1]([CH2:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[O:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:28](Cl)(=[O:38])[O:29][C@@H:30]1[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1>CC#N.CCOC(C)=O>[N:32]12[CH2:37][CH2:36][CH:35]([CH2:34][CH2:33]1)[C@@H:30]([O:29][C:28]([N:1]([CH2:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:38])[CH2:31]2
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Reactant: COC(=O)c1ccc(COc2cccc(CNc3ccccc3)c2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(COc2cccc(CN(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Temperature: 25 °C
Yield: 76 %

Procedure:
A suspension of methyl 4-[[3-(anilinomethyl)phenoxy]methyl]benzoate (380 mg, 1.1 mmol) and (R)-quinuclidin-3-yl carbonochloridate hydrochloride (described in the co-pending International Patent Application No. PCT/EP2013/075529 (published as WO 2014/086855) as Intermediate 16) (300 mg, 1.33 mmol) in anhydrous CH3CN (5 mL) was heated to 100° C. for 15 min under microwave irradiation. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (20 mL) The layers were separated and the organic phase was dried over Na2SO4, filtered and the solvent was removed in vacuo to yield the title compound (419 mg, 76% yield) which was used directly in the next step without any further purification.
Reaction SMILES: COC1N=C2C(=CC=1)N[C@@H](C)C[C@H]2NC(=O)C.[CH:18]1([C@H:21]2[CH2:30][C@@H:29]([NH:31][C:32](=[O:34])[CH3:33])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:35]([F:38])([F:37])[F:36])[N:27]=3)[NH:22]2)[CH2:20][CH2:19]1.Cl[C:40]([O:42][CH:43]([CH3:45])[CH3:44])=[O:41].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH:43]([O:42][C:40]([N:22]1[C:23]2[C:28](=[N:27][C:26]([C:35]([F:37])([F:38])[F:36])=[CH:25][CH:24]=2)[C@H:29]([NH:31][C:32](=[O:34])[CH3:33])[CH2:30][C@@H:21]1[CH:18]1[CH2:20][CH2:19]1)=[O:41])([CH3:45])[CH3:44]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(=O)N[C@@H]1C[C@H](C2CC2)Nc2ccc(C(F)(F)F)nc21
Agent: CN(C)c1ccccn1
Agent: COc1ccc2c(n1)[C@H](NC(C)=O)C[C@H](C)N2
Solvent: c1ccncc1
Product: CC(=O)N[C@@H]1C[C@H](C2CC2)N(C(=O)OC(C)C)c2ccc(C(F)(F)F)nc21
Yield: 31 %

Procedure:
Prepare the title compound by essentially following the procedure described in Example 46, Step 2, by replacing (+/−)-cis-N-(6-methoxy-2-methyl-1,2,3,4-tetrahydro-[1,5]naphthyridin-4-yl)acetamide, with (+/−)-cis-N-(2-cyclopropyl-6-trifluoromethyl-1,2,3,4-tetrahydro-[1,5]naphthyridin-4-yl)acetamide (1.05 g, 3.512 mmol), and using isopropyl chloroformate, pyridine, and dimethylaminopyridine. Purify using silica gel column chromatography (gradient eluent, 0-5% MeOH in ethyl acetate) to provide the title compound (0.416 g, 31%). MS (ES+): 386 (M+H).
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].[C:6](#[N:9])[CH:7]=[CH2:8].C[O-].[Na+]>>[CH2:1]([S:5][CH2:8][CH2:7][C:6]#[N:9])[CH2:2][CH2:3][CH3:4]
Reactant: C=CC#N
Reactant: CCCCS
Agent: C[O-]
Agent: [Na+]
Product: CCCCSCCC#N

Procedure:
β-n-Butylmercaptopropionitrile was prepared according to the procedure of Example 1 using 1-butanethiol (20.0 g; 0.22 moles), acrylonitrile (11.7 g; 0.22 moles) and sodium methoxide (0.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[CH:43]1([NH2:46])[CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:46][CH:43]1[CH2:45][CH2:44]1)=[O:24]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)NC1CC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and cyclopropylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:13])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([Cl:12])[CH:8]=[CH:7][CH:6]=2.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(O)(O)=O>CC#N.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>[Cl:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:2]([C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=1)[C:3]([CH3:13])=[N:4]2
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1nc2cccc(Cl)c2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)O
Solvent: CC#N
Solvent: O
Product: Cc1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
A mixture of 3,5-dichloro-2-methylquinoxaline (Prepared in Example 85, 0.3361 g, 1.577 mmol), 3-fluorobenzeneboronic acid (0.2428 g, 1.735 mmol), tetrakis(triphenylphosphine)palladium (0.09114 g, 0.07887 mmol), and sodium carbonate anhydrous (0.8360 g, 7.887 mmol) in CH3CN—H2O (3:1) (16.00 mL) was stirred at 100° C. After 3.5 h, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give red syrup. The red syrup was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min and then 50% isocratic of EtOAc for 10 min as eluent to give 5-chloro-3-(3-fluorophenyl)-2-methylquinoxaline as a solid: 1H NMR (400 MHz, DMF) δ ppm 8.05 (1H, dd, J=8.4, 1.4 Hz), 8.00 (1H, dd, J=7.6, 1.4 Hz), 7.83 (1H, dd, J=8.4, 7.6 Hz), 7.60-7.67 (3H, m), 7.38-7.46 (1H, m), 2.74 (3H, s); LC-MS (ESI) m/z 273.1 [M+H]+.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH2:10]1[CH2:14]OC[CH2:11]1>C(OCC)C.[Ti]>[C:2]1([C@@H:1]([OH:8])[CH2:14][CH:10]=[CH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C1CCOC1
Agent: [Ti]
Solvent: CCOCC
Solvent: O
Product: C=CC[C@H](O)c1ccccc1
Temperature: -74 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of 1.25 mmol of the titanium compound of Example 2b in 60 ml of diethyl ether is cooled to -74° C., and 0.1 ml (1.0 mmol) of freshly distilled benzaldehyde is added. The slightly yellow, clear solution is stirred for a further 2 hours at -74° C. and 5 ml of a 5N H2O/THF solution are added and the mixture is warmed to RT, stirred for a further hour at this temperature, filtered with suction and concentrated on a rotary evaporator. The crude product (0.80 g of a clear colourless oil) is flash-chromatographed (60 g of silica gel, 35 cm long, cross-section 2 cm, 5 ml/fraction, 0.4 bar, 10:1 toluene/ethanol). 0.098 g of product is obtained. Yield: 66%, ee: 93%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([C:17]3[CH:18]=[N:19][C:20]([O:23]C)=[CH:21][CH:22]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1>Br>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[N:19][CH:18]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-n2c(-c3cccc(F)c3)nc3cccnc32)cn1
Agent: Br
Product: Oc1ccc(-n2c(-c3cccc(F)c3)nc3cccnc32)cn1
Temperature: 100 °C
Reaction time: 0.58 h
Yield: 62.2 %

Procedure:
A mixture of 1.80 g of 2-(3-fluorophenyl)-3-(6-methoxy-3-pyridyl) -3H-imidazo[4,5-b]pyridine and 20 mL of 47% hydrobromic acid was stirred at 100° C. for 3 hours and 35 minutes. The reaction mixtures was evaporated, to give a brown oil. This oil was subjected 3 times to azeotropic distillation with toluene, and the resulting brown oil was subjected to crystallization from methanol, to give 1.07 g of the title compound as greenish brown crystals (63% y.).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[C:20](=[O:21])[C:19]2([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[O:18][C:17]1=[O:27].[CH2:30](Br)[CH3:31].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C.O>[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[C:20](=[O:21])[C:19]2([CH2:22][CH2:23][N:24]([CH2:30][CH3:31])[CH2:25][CH2:26]2)[O:18][C:17]1=[O:27]
Reactant: CCBr
Reactant: CC(C)(C)Cn1c(CN2C(=O)OC3(CCNCC3)C2=O)cc2cnc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCC2(CC1)OC(=O)N(Cc1cc3cnc(C#N)nc3n1CC(C)(C)C)C2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 7-(2,2-dimethyl-propyl)-6-(2,4-dioxo-1-oxa-3,8-diaza-spiro[4.5]dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.63 mmol) in DMF (2 ml) are added ethyl bromide (0.69 mmol), K2CO3 (0.76 mmol), and NaI (0.95 mmol). The mixture is allowed to stir at ambient temperature under nitrogen atmosphere for 18 hours. The reaction mixture is diluted with H2O and extracted with AcOEt. The organic layer is washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by HPLC(H2O—0.1% TFA/acetonitrile—0.1% TFA). Fractions are collected, basified with 5% aqueous NaHCO3, extracted with AcOEt, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give 7-(2,2-dimethyl-propyl)-6-(8-ethyl-2,4-dioxo-1-oxa-3,8-diaza-spiro[4.5]dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile.