Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=[O:4].CO.[NH3:24]>>[Br:12][C:9]1[CH:10]=[CH:11][C:6]2[NH:5][C:3](=[O:4])[CH2:2][N:24]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:7]=2[CH:8]=1
Reactant: O=C(CBr)Nc1ccc(Br)cc1C(=O)c1ccccc1F
Reactant: N
Solvent: CO
Product: O=C1CN=C(c2ccccc2F)c2cc(Br)ccc2N1
Temperature: 25 °C

Procedure:
The product from Step 1 (21.17 g, 51 mmol) was dissolved in ammonia, 2M in methanol (400 mL, 800 mmol) that was further saturated with anhydrous ammonia. The solution was heated to reflux for 16 hr overnight, and allowed to cool to room temperature. The solution was concentrated and the residue was dissolved in ethyl acetate and water. The ethyl acetate layer was washed twice with water, dried with brine, and concentrated to give a yellow solid. The solid was recrystallized from ethyl acetate/hexane to give a white powder that was washed with hexane and air dried (9.65 g, 56.8%).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)=[CH:12][CH:11]=2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:14][CH:15]=1
Reactant: O=C1CCC(c2ccc(OCCCN3C(=O)c4ccccc4C3=O)cc2)=NN1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCOc1ccc(C2=NNC(=O)CC2)cc1
Temperature: 25 °C
Yield: 51.6 %

Procedure:
A solution of 2.748 g (7.28 mmol) of the phthalimide prepared above and 398 microliters (8.0 mmol) of 98% hydrazine hydrate in 75 ml of ethanol is heated overnight at reflux under N2. After cooling to RT, the volatiles are removed under vacuum. The residual white solid is taken up in 15 ml of 70:30 CH3OH:NH4OH and flash chromatographed on silica gel (90:10:2 CHCl3 :CH3OH:NH4OH) to give 929 mg of 6-[4-(3-aminopropyloxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone as a white solid. Yield, 23%.
Reaction SMILES: C[Si]([CH:5]=[N+:6]=[N-:7])(C)C.[CH3:8][CH:9]([CH3:20])[CH2:10][C:11](=[O:19])[C:12]#[C:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH3:8][CH:9]([CH3:20])[CH2:10][C:11]([C:12]1[NH:7][N:6]=[CH:5][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCOC(=O)C#CC(=O)CC(C)C
Product: CCOC(=O)c1cn[nH]c1C(=O)CC(C)C

Procedure:
(Trimethylsilyl)diazomethane (2.0M in hexanes, 25 ml) was added slowly with stirring under nitrogen to ethyl 6-methyl-4-oxo-2-heptynoate (7.0 g) in drytetrahydrofuran (20 ml) in a cold water bath. After 16 hours the reaction was evaporated to an oil, which was subjected to chromatography on silica (ethyl acetate/isohexane 1:2) to give the first eluted product, ethyl 5-(3-methyl-1-oxobutyl)-1H-pyrazole4-carboxylate (2.33 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].CS([C:42]1[N:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][N:43]=1)(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:42]3[N:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][N:43]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: CS(=O)(=O)c1ncc(C(F)(F)F)cn1
Product: COc1ccc(CC2c3cc(Oc4ncc(C(F)(F)F)cn4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2-methane-sulfonyl-5-trifluoromethyl-pyrimidine
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([NH:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([F:13])[CH:7]=2)#[N:2].[NH2:27][NH2:28].O>CO>[F:13][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]=[C:3]([C:1]([NH:27][NH2:28])=[NH:2])[N:4]=[C:5]2[NH:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[CH:10][CH:9]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3ccc(F)cc23)C1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C(=N)NN)cc3ccc(F)cc23)C1

Procedure:
To a mixture of (S)-tert-butyl 3-((3-cyano-7-fluoroisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (350 mg, 1 mmol) in MeOH (10 mL) was added NH2NH2—H2O (10 mL). The reaction mixture was heated to reflux for 2 hours. The solvent was removed to give the title compound as white solid, which was used without further purification (350 mg, 92%). ESI-MS m/z [M+H]+ 389.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](=[N:10]/[OH:11])/[CH3:9].Cl[CH2:13][CH2:14][CH2:15][OH:16]>>[OH:16][CH2:15][CH2:14][CH2:13][O:11]/[N:10]=[C:8](/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])\[CH3:9]
Reactant: OCCCCl
Reactant: C/C(=N\O)c1ccccc1N
Product: C/C(=N\OCCCO)c1ccccc1N

Procedure:
In Scheme 3, Compound (α1) is reacted with hydroxylamine hydrochloride to obtain (E)-1-(2-aminophenyl)ethanone oxime (Compound (a4)). Compound (a4) is reacted with 3-chloropropan-1-ol to obtain (E)-1-(2-aminophenyl)ethanone O-3-hydroxypropyl oxime (Compound (a5)). Compound (a5) is then reacted with p-pivaloyloxybenzenesulfonyl chloride to obtain the compound of formula (I). The following Compound (7) in Preparation Examples 6 was prepared using Scheme 3.
Reaction SMILES: [ClH:1].[CH:2]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3]1>C(O)C>[Cl:1][CH2:4][CH2:3][CH2:2][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)=[O:6]
Reactant: CCOC(=O)C(Cc1ccc(C(=O)C2CC2)cc1)C(=O)OCC
Reactant: Cl
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(C(=O)CCCCl)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
Bubble hydrogen chloride gas through a solution of [4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, diethyl ester (570 mg, 2.0 mmol) in ethanol (4 mL) for 5 minutes. Heat the solution to reflux. After 18 hours, cool the solution to room temperature and bubble nitrogen through the solution for 1 hour. Add ethyl acetate and water to the residue. Dry the organic phase over anhydrous magnesium sulfate and concentrate. Dissolve the crude product in ethanol (50 mL) and bubble hydrogen chloride gas through the solution for 10 minutes. Heat the solution to reflux. After stirring 2 days, concentrate the solution. Add water and ethyl acetate to the residue. Dry the organic phase over anhydrous magnesium sulfate and concentrate. Purify by flash chromatography (150 g silica gel, 20% ethyl acetate/heptane as eluent) to give the title compound (409 mg, 59%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1.Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>Cl>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[NH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:8][CH2:9]1
Reactant: Clc1ccc2ccccc2n1
Reactant: COc1ccccc1N1CCN(CCN)CC1
Agent: Cl
Product: COc1ccccc1N1CCN(CCNc2ccc3ccccc3n2)CC1
Reaction time: 18 h
Yield: 12.4 %

Procedure:
1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine (9.4 g, 40 mmol) and 2-chloroquinoline (6.5 g, 40 mmol) were heated at 160° C. for 3 h, then at 120° C. for 18 h in a sealed vessel. The resultant brown tar was taken up into dilute hydrochloric acid (300 ml), washed with dichloromethane (3×100 ml) basified with sodium hydroxide, extracted into dichloromethane (3×100 ml), dried (MgSO4) then evaporated in vacuo to give a brown oil. The oil was purified by chromatography [alumina; ethyl acetate-toluene (1:4)] to give the product (1.8 g) as a clear oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C[Sn](C)(C)[C:15]1[S:16][CH:17]=[CH:18][N:19]=1>>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: C[Sn](C)(C)c1nccs1
Reactant: O=Cc1cc(Br)cc2ccoc12
Product: O=Cc1cc(-c2nccs2)cc2ccoc12

Procedure:
From 5-Bromo-benzofuran-7-carbaldehyde (400 mg) and 2-trimethylstannanylthiazole (1.22 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:49]([C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH2:63])[CH:58]=2)=[CH:53][C:52]=1[F:64])#[N:50]>CN(C=O)C>[C:49]([C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=2)=[CH:53][C:52]=1[F:64])#[N:50]
Reactant: N#Cc1ccc(-c2cccc(N)c2)cc1F
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
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
Product: N#Cc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc1F
Temperature: 25 °C
Yield: 15.4 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-cyano-3′-fluoro-biphenyl-3-ylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.004 g of product in 15% yield: LCMS (ESI) m/z 401 (MH+).
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[F:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47](Cl)=[O:48])=[CH:42][CH:41]=1>C(Cl)Cl>[C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][N:16]([C:47](=[O:48])[CH2:46][C:43]3[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=3)[CH2:17][C:18]=2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CN(C(=O)Cc1ccc(F)cc1)CC2(C)C
Temperature: 25 °C
Yield: 11.8 %

Procedure:
To a solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (10.1 mg, 0.024 mmol) in CH2Cl2 (5 mL) was added Et3N (9.85 μl, 0.071 mmol) followed by 2-(4-fluorophenyl)acetyl chloride (6.10 mg, 0.035 mmol) and the resulting mixture stirred at room temperature. (Mixture became a clear, colorless solution within 30 min.) After 3 h, the solvent was removed and the residue was taken up in MeOH/DMF and purified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm). The product containing fractions were concentrated to remove the organic solvent and the resulting precipitate isolated by filtration and washed with water to give 2-tert-butoxy-2-(4-(4-fluorophenyl)-6-(2-(4-fluorophenyl)acetyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (1.6 mg, 11.78% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.13-7.53 (5H, m), 6.88-7.09 (3H, m), 4.80-4.88 (1H, m), 4.32-4.46 (0.5H, m), 4.18-4.32 (1H, m), 3.97 (0.5H, d, J=16.56 Hz), 3.79-3.92 (1.5H, m), 3.55-3.68 (3H, m), 3.52 (0.5H, d, J=13.05 Hz), 1.37 (3H, d, J=6.53 Hz), 1.32 (3H, d, J=7.53 Hz), 1.27 (3H, dd, J=6.27, 5.02 Hz), 1.15 (3H, dd, J=6.53, 4.77 Hz), 0.91-1.06 (9H, m). 19F NMR (400 MHz, CD3OD) δ ppm −114.90, −115.19, −117.98, −118.41. LCMS (M+H) calcd for C33H39F2N2O4: 565.28. found: 565.4.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH:17][O:18]C)=[O:16])=[C:11]([F:20])[CH:10]=2)[CH2:4]1.C(N(CC)CC)C.[C:28](SCC)(=[S:30])[CH3:29]>CN(C=O)C>[C:28]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH:17][OH:18])=[O:16])=[C:11]([F:20])[CH:10]=2)[CH2:4]1)(=[S:30])[CH3:29]
Reactant: CONC(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Reactant: CCSC(C)=S
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=S)NC[C@H]1CN(c2ccc(C(=O)NO)c(F)c2)C(=O)O1

Procedure:
A solution of 5-(S)-aminomethyl-3-[4′-(N-methoxyamino)carbonyl-3′-fluorophenyl]-oxazolidine-2-one (0.053 ml, 0.47 mmol), triethylamine (0.12 ml, 0.84 mmol) and ethyl dithioacetate (0.87 ml, 7.6 mmol) in DMF (0.75 ml) was stirred at r.t. for 48 h. Solvent was removed under vacuum, and the crude material purified by silica gel PTLC (eluent: 5% MeOH in ethyl acetate). White crystalline solid (100 mg, 70%). HPLC Rt=4.6 min. MS (m/z): [M+H]+=342.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([CH3:37])=[CH:29]2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][C:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:28]([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:21]=2)=[O:27])[CH:29]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cn(C(=O)c2cc(Cl)ncn2)c2ccccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cn(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
227 mg (0.78 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one dihydrochloride were added to 200 mg (0.74 mmol) (6-chloropyrimidin-4-yl)-(3-methyl-indol-1-yl)-methanone and 413 μL (2.40 mmol) DIPEA in 5 mL DMF. The reaction mixture was stirred overnight at RT and then purified by preparative HPLC. The product fractions were combined and concentrated by rotary evaporation using the rotary evaporator. The residue was taken up in methanol and purified through a silica gel column. The product fractions were combined and concentrated by rotary evaporation using the rotary evaporator.
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:6][CH:5]([NH2:7])[CH2:4]1.C(Cl)Cl.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(N(CC)CC)C>[F:2][C:3]1([F:8])[CH2:6][CH:5]([NH:7][S:13]([CH3:12])(=[O:15])=[O:14])[CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: NC1CC(F)(F)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC1CC(F)(F)C1
Reaction time: 16 h

Procedure:
0.60 g 3,3-Difluoro-cyclobutylamine hydrochloride were suspended using 40 ml CH2Cl2 and 2.9 ml of triethylamine added at ambient temperature while receiving a clear solution. Thereafter, 1.0 ml of methanesulfonylchloride were added dropwise at ambient temperature and the mixture left at that temperature for 16 h. The volatiles were removed in vacuo, the residue was redissolved using 200 ml of EE and 100 ml of a saturated aqueous Na2CO3-solution and the layers separated. The organic layer was washed twice using 20 ml of a saturated aqueous NaHSO4-solution each time and washed twice using 30 ml of a saturated aqueous Na2CO3-solution each time. The organic layer was dried over MgSO4 and the solvent removed in vacuo. Yield: 700 mg of a colorless resin.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:20])[CH:12]=[CH:11]3)[CH2:8]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C)C=O>[N:21]([CH2:6][CH:7]1[O:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:20])[CH:12]=[CH:11]3)[CH2:8]1)=[N+:22]=[N-:23]
Reactant: CS(=O)(=O)OCC1Cc2c(ccc3[nH]c(=O)ccc23)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1Cc2c(ccc3[nH]c(=O)ccc23)O1
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
The compound obtained in Example 157 (1.0 g, 3.37 mmol) and sodium azide (1.9 g, 33.7 mmol) were suspended in dimethylformamide (20 ml). The suspension was stirred at 100° C. for 2 hours, followed by cooling. The reaction mixture was combined with water, and the precipitated crystals were collected by filtration and washed with water. 0.733 g of the title compound was obtained as pale brown crystals (89.4%, mp.: 194° C. (dec.)).
Reaction SMILES: C([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][CH2:13][CH:12]2[OH:22])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.C(OC(=O)C)C.[Pd]>[C:16]1([N:15]2[C:11]3([CH2:23][CH2:24][NH:8][CH2:9][CH2:10]3)[CH:12]([OH:22])[CH2:13][CH2:14]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OC1CCN(c2ccccc2)C12CCN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: OC1CCN(c2ccccc2)C12CCNCC2

Procedure:
(RS)-8-Benzyl-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol (7.8 mmol) was dissolved in methanol (100 ml) and ethylacetate (100 ml). Palladium on carbon (10%, 0.2 g) was added and the mixture was hydrogenated at room temperature and normal pressure. Filtration and evaporation yielded the desired product. 1.8 g (99%) (RS)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol as a beige solid, m.p. 141-144° C. and MS: m/e=232 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:18][O:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[F:28])=[C:15]3[C:10]([CH:11]=[C:12]([F:36])[C:13]([F:35])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[N-:37]=[N+:38]=[N-:39].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[CH2:18][O:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]4[N:37]=[N:38][NH:39][N:25]=4)=[CH:22][C:21]=3[F:28])=[C:15]3[C:10]([CH:11]=[C:12]([F:36])[C:13]([F:35])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(OCC(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Fc1cc2nn(-c3ccc(Cl)cc3)c(C(COc3ccc(-c4nn[nH]n4)cc3F)C3CCCCC3)c2cc1F

Procedure:
In analogy to the procedure described in example 31, [rac]-4-{2-[2-(4-Chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-3-fluoro-benzonitrile was reacted with sodium azide in the presence of triethylamine hydrochloride in DMF to obtain the title compound as colorless oil. MS: m/e=553.3 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])=[C:5]([CH3:14])[O:4][N:3]=1.C(O[CH:18]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:10][CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:11]=[CH:12][CH:13]=2)=[C:5]([CH3:14])[O:4][N:3]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1noc(C)c1-c1cccc(N)c1
Product: CCOC(=O)C(=CNc1cccc(-c2c(C)noc2C)c1)C(=O)OCC
Temperature: 130 °C
Yield: 52 %

Procedure:
3-(3,5-Dimethyl-4-isoxazolyl)aniline (for a preparation see Intermediate 2, 80 g, 420 mmol) and diethyl ethoxymethylenemalonate (92 g, 425 mmol) were mixed together and heated to 130° C. for 20 minutes, liberating ethanol, which was evaporated under reduced pressure. The reaction mixture was poured into iPr2O (1 L) and the resulted precipitate filtered off and washed with iPr2O. The resulting solid was recrystallised from acetonitrile to give the title compound as a brown solid (78 g, 52%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:18]=1[CH:19]=[O:20]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(O)c(C=O)c1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)cc3C=O)c2cc1OC
Temperature: 160 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (113 mg), 2-hydroxy-5-methylbenzaldehyde (344 mg), and 4-dimethylaminopyridine (313 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 2 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue. The organic layer was washed with a 1 N aqueous sodium hydroxide solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by column chromatography using chloroform to give the title compound (157 mg, yield 96%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][N:22]=3)[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)C2CCNCC2)cc1
Reactant: Clc1nccc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)C2CCN(c3nccc4ccccc34)CC2)cc1
Yield: 18.5 %

Procedure:
Using the procedure from Example 7A, 4-[(4-tert-butylphenyl)sulfonyl]piperidine (150 mg, 0.53 mmol) was reacted with 1-chloroisoquinoline (183 mg, 1.06 mmol), DIEA (0.37 ml, 2.12) and 1,4-dioxane (0.2 ml) at 185° C. to afford the title compound (40 mg), a white solid, in 18% yield.