Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(CCCC)(CCCC)CCCC.[N+:14](=[C:16]([C:22]([C:24]1[CH:29]=[C:28]([CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:27]=[CH:26][C:25]=1F)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-:15]>O1CCOCC1>[OH:23][C:22]1[C:24]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:29]=2)[N:15]=[N:14][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)c1cc(CN2CCOCC2)ccc1F
Agent: CCCCP(CCCC)CCCC
Solvent: C1COCCO1
Product: CCOC(=O)c1nnc2ccc(CN3CCOCC3)cc2c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.7 %

Procedure:
A solution of Bu3P (3.90 iL) in dioxane (20 mL) is added to a stirred solution of ethyl 2-diazo-3-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-3-oxopropanoate (Preparation 7, 3.16 g) in dry dioxane (56 mL). The mixture is stirred at room temperature for 30 min then gently refluxed for 1.5 h. The reaction is cooled and concentrated. The crude product is purified by column chromatography (CH2Cl2/MeOH, 99/1; CH2Cl2/MeOH, 98/2; CH2Cl2/MeOH, 95/5) to yield 0.200 g (4.5%) of the desired product as an off-white solid. Additional material can be obtained by heating the acyclic intermediate which was isolated in the chromatography at 130° C. in diglyme (32 mL) for 3.5 h. The resulting mixture is concentrated. The crude product is purified by column chromatography (CH2Cl2/MeOH, 99/1; CH2Cl2/MeOH, 98/2; CH2Cl2/MeOH, 95/5) to yield 0.531 g (30% %) of the desired product as a white solid to give an overall yield of 0.731 g (35%). Physical characteristics are as follows: m.p. 195-197° C. (dec); 1H NMR (DMSO-d6) δ 14.0, 8.01, 7.83, 7.67, 4.30, 3.60, 2.38, 1.30; MS (ESI-) for C16H19N3O4 m/z 316.1 (M—H)−.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([C:17]#[N:18])[CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:6]([F:19])[C:5]([CH2:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[NH:23][N:22]=2)=[CH:4][CH:3]=1.ClC1C=C(C=[C:36]([O:38]C2C(Cl)=CC=C(CC3C=C(C)C(=O)NN=3)C=2F)C=1)C#N.ClC1C(OC2C=C(C=C(C(F)F)C=2)C#N)=C(F)C(CC2C=C(C)C(=O)NN=2)=CC=1>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([C:17]#[N:18])[CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:6]([F:19])[C:5]([CH2:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH2:36][OH:38])[N:22]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Cc2ccc(Cl)c(Oc3cc(C#N)cc(C#N)c3)c2F)n[nH]c1=O
Reactant: Cc1cc(Cc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)n[nH]c1=O
Agent: Cc1cc(Cc2ccc(Cl)c(Oc3cc(C#N)cc(C(F)F)c3)c2F)n[nH]c1=O
Product: Cc1cc(Cc2ccc(Cl)c(Oc3cc(C#N)cc(C#N)c3)c2F)nn(CO)c1=O

Procedure:
Compounds I-22, I-27 and I-29 can be prepared in similar manner except 5-[6-chloro-2-fluoro-3-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenoxy]-isophthalonitrile was replaced with 3-chloro-5-[6-chloro-2-fluoro-3-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenoxy]-benzonitrile, 3-[6-chloro-2-fluoro-3-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenoxy]-5-difluoromethyl-benzonitrile and 3-[6-chloro-2-fluoro-3-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenoxy]-5-difluoromethyl-benzonitrile respectively.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[O:6][C@H:5]2[C@H:7]([N:12]3[CH:20]=[N:19][C:18]4[C:13]3=[N:14][CH:15]=[N:16][C:17]=4[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)[CH:22]=3)[O:8][C@H:9]([CH2:10][OH:11])[C@H:4]2[O:3]1.Cl[S:34]([NH2:37])(=[O:36])=[O:35]>>[S:34](=[O:36])(=[O:35])([O:11][CH2:10][C@@H:9]1[C@@H:4]2[C@@H:5]([O:6][C:2]([CH3:32])([CH3:1])[O:3]2)[C@H:7]([N:12]2[CH:20]=[N:19][C:18]3[C:13]2=[N:14][CH:15]=[N:16][C:17]=3[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)[CH:22]=2)[O:8]1)[NH2:37]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(-c3cccc(-n4cccn4)c3)ncnc21
Reactant: NS(=O)(=O)Cl
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(-c3cccc(-n4cccn4)c3)ncnc21
Yield: 88 %

Procedure:
Using essentially the same procedure as Example 43, step f, ((3aR,4R,6R,6aR)-2,2-dimethyl-6-{6-[3-(1H-pyrazol-1-yl)phenyl]-9H-purin-9-yl}tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (0.2 g, 0.46 mmol) was reacted with chlorosulfonamide, as described in Example 43, step f, and the product was purified by flash chromatography using 40-75% ethyl acetate/hexanes to give the title compound as a yellow solid (0.208, 88%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8]([CH2:17][NH2:18])([C:13]([F:16])([F:15])[F:14])[C:7]=2[CH:19]=1.C(N(CC)CC)C.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.O>C1COCC1.C(OCC)(=O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8]([CH2:17][NH:18][S:34]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)(=[O:36])=[O:35])([C:13]([F:15])([F:16])[F:14])[C:7]=2[CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(Cl)cc2C(CNS(=O)(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
While stirring a solution of [6-chloro-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methylamine hydrochloride (60 mg, 0.19 mmol) in THF (1 mL) at room temperature, triethylamine (66 μL, 0.47 mmol) and 4-fluorobenzenesulfonyl chloride (44 mg, 0.23 mmol) were sequentially added thereto. After the reaction solution was stirred overnight at room temperature, water was added thereto. Then, the resulting solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by thin-layer silica gel column chromatography (ethyl acetate/hexane=1/1), whereby the objective compound (58 mg, 70%) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.Cl[P:19]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(OCC)C>[CH:26]1([P:19]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[O:12][CH2:11][CH2:10][O:9]3)=[CH:4][CH:3]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Reactant: Brc1ccc(C2OCCO2)cc1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: c1cc(P(C2CCCCC2)C2CCCCC2)ccc1C1OCCO1
Temperature: 25 °C

Procedure:
This is an example of synthesis of ligand 2. 2-(4′-Dicyclohexylphosphinophenyl)-1,3-dioxolane (Ligand 2): Part I. A solution of 4-bromobenzaldehyde (5 g, 0.027 mol), ethylene glycol (7.0 g, 0.11 mmol), and p-toluenesulfonic acid (0.1 g, 0.5 mmol) in benzene was heated at reflux for 24 h using a Dean-Stark setup to remove water. The reaction was taken up in diethyl ether (100 mL) and washed with water (5×30 mL) and brine (30 mL). The organic phase was dried over magnesium sulfate and concentrated under vacuum to afford 2-(4′-bromophenyl)-1,3-dioxolane (5.95 g). Part II. 2-(4′-bromophenyl)-1,3-dioxolane (1.0 g, 4.4 mmol) was dissolved in anhydrous diethyl ether (30 mL) and the solution was cooled to −78° C. t-Butyllithium (5.14 mL, 1.7 M solution in pentane, 8.8 mmol) was added dropwise with stirring. The reaction was stirred for 2 h at −78 ° C. Chlorodicyclohexylphosphine (1.13 g, 4.8 mmol) was added dropwise via a syringe at −78 ° C. with stirring. The reaction mixture was allowed to warm up to room temperature and stirred for an additional 18 h. To the reaction mixture was added argon purged water (25 mL) slowly. The organic phase was separated under argon and the aqueous phase was washed with diethyl ether (20 mL). The combined organic phase was concentrated under vacuum to afford a colorless oil, which was crystallized from methanol to afford ligand 2 as a white crystalline solid having the structure shown below (yield: 1.4 g, 92%). 31P{1H} NMR (CDCl3): δ2.4.
Reaction SMILES: [CH2:1]([C:3]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:12]([OH:14])=O)[CH:4]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][CH2:28][C:29]12[CH2:36][CH2:35][CH2:34][N:33]1[CH2:32][CH2:31][CH2:30]2>CN(C)C=O>[CH2:1]([C:3]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:12]([NH:27][CH2:28][C:29]23[CH2:36][CH2:35][CH2:34][N:33]2[CH2:32][CH2:31][CH2:30]3)=[O:14])[CH:4]=1)[CH3:2]
Reactant: NCC12CCCN1CCC2
Reactant: CCc1cc(C(=O)O)c2ccccn12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NCC23CCCN2CCC3)c2ccccn12

Procedure:
3-Ethylindolizine-1-carboxylic acid is reacted with carbonyldiimidazole in dimethylformamide and subsequently with 7a-aminomethylhexahydro-1H-pyrrolizine to afford the title compound upon workup.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[Cl:7][C:8]1[N:13]=[N:12][C:11]([NH2:14])=[CH:10][CH:9]=1>C(#N)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:5]=[C:3]([CH2:2][Cl:1])[N:14]=2)[N:13]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: O=C(CCl)CCl
Solvent: CC#N
Product: ClCc1cn2nc(Cl)ccc2n1
Yield: 38.5 %

Procedure:
1,3-Dichloroacetone (21.4 g, 168.0 mmol) was added to a solution of 6-chloropyridazin-3-amine (10 g, 77.2 mmol) in acetonitrile (200 ml). The mixture was heated at reflux for 14 h (the reaction was monitored by TLC). The volatiles were removed under reduced pressure and the reaction mixture was diluted with water. The pH was adjusted to ˜7.5 with sodium bicarbonate solution and then extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 14% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 6-chloro-2-(chloromethyl) imidazo[1,2-b]pyridazine (6.0 g, 64.1%) as white solid. 1H NMR: 200 MHz, CDCl3: δ 8.0 (s, 1H), 7.9 (d, 1H), 7.1 (d, 1H), 4.75 (s, 2H). MS: [M+H]+: m/z=202.8.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=O)/[CH:12]=[CH:13]/N(C)C)[NH:8][CH:7]=1)=[O:5])[CH3:2].Cl.[NH2:19][C:20]([NH2:22])=[NH:21].CC[O-].[Na+]>C(O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][N:19]=[C:20]([NH2:22])[N:21]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c(C(=O)/C=C/N(C)C)c1
Reactant: N=C(N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c[nH]c(-c2ccnc(N)n2)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
To a suspension of 5-((E)-3-Dimethylamino-acryloyl)-1H-pyrrole-3-carboxylic acid ethyl ester (0.25 g, 1.06 mmol) in 4 mL of ethanol, guanidine hydrochloride (0.121 g, 1.27 mmol) and sodium ethylate (0.086 g, 1.27 mmol) were added. The mixture was heated to 110° C. overnight. Then, a further amount of sodium ethylate (0.086 g, 1.27 mmol) was added to the mixture and heating to 115° C. was prolonged for additional 24 hours. The resulting mixture was cooled at room temperature and diluted with water (2 mL). The solid was isolated by filtration, washed with 10 mL of water, dried in a vacuum oven at 40° C. affording to give 0.197 g (80%) of the title compound.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[NH:21][N:20]=[N:19][C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)=[N:8]1.Cl>CO>[NH:7]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[NH:21][N:20]=[N:19][C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)=[N:8]1
Reactant: C[Si](C)(C)CCOCn1ccc(-c2nc(N)nc3nn[nH]c23)n1
Agent: Cl
Solvent: CO
Product: Nc1nc(-c2cc[nH]n2)c2[nH]nnc2n1
Reaction time: 2 h
Yield: 104.1 %

Procedure:
A solution of 7-(1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-3-yl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (120 mg, 0.361 mmol) in MeOH (2 mL) was treated with HCl (4-M in dioxan, 1 mL), stirred for 2 h, filtered and the resulting solid washed with Et2O to give the title compound (76 mg, 100%) as a yellow solid.
Reaction SMILES: S1C=CC=C1C=O.C(O)(=O)CC(O)=O.[NH:15]1CCCCC1.[OH-].[Na+].[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1/[CH:28]=[CH:29]/[C:30]([OH:32])=O.C(Cl)(=O)C(Cl)=O.O.N>N1C=CC=CC=1.ClCCl.CN(C=O)C.O>[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1/[CH:28]=[CH:29]/[C:30]([NH2:15])=[O:32]
Reactant: C1CCNCC1
Reactant: O=C(O)/C=C/c1cccs1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: NC(=O)/C=C/c1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.12 g of 2-thiophene carboxaldehyde and 3.12 g of malonic acid were dissolved in 15 ml of pyridine, added with a catalytically effective amount of piperidine, reacted at 80° C. for 6 h, the reaction solution was poured into 20 ml of water, regulated with 10% NaOH aqueous solution to reach PH 12, extracted with ethyl acetate, the water layer was taken and regulated with 2N hydrochloric acid to reach PH3, a large amount of yellow solid (2E)-3-(2-thienyl)acrylic acid was precipitated, filtered and washed with water to obtain 1.12 g. The (2E)-3-(2-thienyl)acrylic acid was dissolved in 10 ml of anhydrous dichloromethane, added with a catalytically amount of DMF, added dropwise with 1.5 ml of oxalyl chloride under ice-water bath, after adding dropwise, heated to room temperature, stirred for 2 h, the reaction solution was added dropwise into 0° C. 10 ml concentrated ammonia water, stirred for 30 min, the layers were separated, the dichloromethane layer was taken, evaporated to remove solvent and obtain white needle crystal (2E)-3-(2-thienyl)acrylamide 0.7 g. It together with 1.20 g of trichloroacetaldehyde hydrate was added to 30 ml of toluene, refluxed at 110° C. for 8 h, cooled to room temperature to precipitate a large amount of yellow lamellar crystal (2E)-3-(2-thienyl)-N-(1-hydroxy-2,2,2-trichloroethyl)acrylamide 1.20 g. It was dissolved in 20 ml anhydrous THF, added with DMF for catalysis, added dropwise with SOCl2 1.2 ml at room temperature, heated to 60° C. and reacted for 2 h. After solvent was evaporated, it was dissolved in anhydrous acetone, added with 0.3 g of KSCN, stirred and reacted at 40° C. for 2 h, filtered with diatomite, the filtrate was eluted with developing solvent system of petroleum ether:ethyl acetate=20:1, to obtain yellow needle crystal (2E)-3-(2-thienyl)-N-(1-isothiocyano-2,2,2-trichloroethyl)acrylamide 0.81 g. It was dissolved in 10 ml of THF, added with 0.30 g of 8-aminoquinoline, heated to 60° C. and reacted for 2 h, cooled to room temperature to precipitate a large amount of white flocculent solid (2E)-3-(2-thienyl)-N-[1-(8-quinolylamino)thioformylamino-2,2,2-trichloroethyl]-2-acrylamide, which was recrystallized with THF to obtain a pure product of 0.92 g. 1H-NMR(400 MHz, DMSO-d6)δ6.63-6.67(d,1H); δ7.12-7.14(q,1H); δ7.42-7.43(d,1H); δ7.53-7.73(m, 6H); δ8.42-8.44(dd,1H); δ8.95-9.03(m,3H); δ9.54-9.56(d,1H); δ11.03(s,1H). MS(TOF) 487.0 (M+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[Si:12](OC(CCC)CC(OCC)=O)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[Si:12]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CCCC(CC(=O)OCC)O[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)CCCCCO
Product: CCOC(=O)CCCCCO[Si](C)(C)C(C)(C)C
Yield: 90 %

Procedure:
Ethyl 6-((tert-butyldimethylsilyl)oxy)hexanoate 8 (3.08 g) was prepared in 90% yield using ethyl 6-hydroxyhexanoate 7 according to the procedures described for compound 2 in above (see Schemes 1-3).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH:10]=[O:11])[CH2:4][CH2:3]1.CC1C=CC(C=O)=CC=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=[O:11])=[CH:4][CH:3]=1
Reactant: CC1CCC(CCC=O)CC1
Agent: Cc1ccc(C=O)cc1
Product: Cc1ccc(CCC=O)cc1

Procedure:
4-Methyl cyclohexanepropanal was similarly prepared as described in Examples I and II. First, 4-methyl benzaldehyde (140 g, commercially available from Mitsubishi Gas Chemical Company, Inc.) was used to obtain 3-(4-methyl-phenyl)-propionaldehyde (130 g) with a boiling point of 120° C. at a pressure of 21 mmHg. 3-(4-Methyl-phenyl)-propionaldehyde (180 g) was consequently used to provide 4-methyl cyclohexanepropanal (104 g) with a boiling point of 112° C. at a pressure of 24 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1[N+:16]([O-])=O>CO.[H][H].[Pd]>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1[NH2:16]
Reactant: [H][H]
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(OC)c(OC)c(OC)c1N
Yield: 92.6 %

Procedure:
The latter nitro derivative (17.0 g) in 500 ml of methanol was reduced at room temperature and pressure with hydrogen using 4 g of 10% palladium on carbon as catalyst for 6 hr and filtered. The solvent was removed to give 14 g of 2-amino-3,4,5-trimethoxybenzoic acid methyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:22]([O:23][CH3:24])=[CH:21][C:6]2[S:7][C:8]([CH:19]=O)=[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:26]=1.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3]1[C:22]([O:23][CH3:24])=[CH:21][C:6]2[S:7][C:8](/[CH:19]=[C:31](\[C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)/[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:5]=2[CH:4]=1
Reactant: CCOC(=O)Cc1ccncc1
Reactant: COc1ccc(Oc2c(C=O)sc3cc(OC)c(OC)cc23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)/C(=C/c1sc2cc(OC)c(OC)cc2c1Oc1ccc(OC)cc1)c1ccncc1
Temperature: 100 °C

Procedure:
A solution containing 6 mmol of the product obtained in Step E, 30 mmol of ethyl 4-pyridylacetate and 5 ml of acetic anhydride is maintained at 100° C. for 18 hours. After returning to room temperature, the reaction mixture is hydrolysed by a saturated NaHCO3 solution and extracted with ethyl acetate. The organic phases are then washed with water and then with an NaCl solution, dried over calcium sulphate, filtered and concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ethanol: 98/2) enables the expected product to be isolated.
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]([CH3:13])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6]>C(O)(=O)C>[Br:1][C:4]([CH3:13])([CH3:3])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6]
Reactant: CC(C)C(=O)c1ccccn1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)(Br)C(=O)c1ccccn1
Temperature: 105 °C

Procedure:
Bromine (2.1 g, 13.4 mmol) dissolved in acetic acid (1 mL) was added slowly to a mixture of 2-methyl-(1-pyridin-2-yl)propan-1-one (2.0 g, 13 mmol) in acetic acid (20 mL) at room temperature. The reaction was heated to 105° C. for 3 h, allowed to cool to room temperature, and concentrated in vacuo to give a dark semisolid. The crude product was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 2-bromo-2-methyl-1-(pyridin-2-yl)propan-1-one as a very dark oil (3.0 g, 98%). LCMS calculated for C9H11BrNO (M+H)+: m/z=227.9, 229.9. found: 228.1, 230.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:13]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[CH2:13]([C@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH3:14]
Reactant: C=C[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC[C@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
Tert-butyl-(2R)-2-vinylpyrrolidine-1-carboxylate (0.21 g, 1.07 mmol) was dissolved in methanol (10 mL) with palladium on carbon, 10% catalyst (0.046 g, 20% by wt.) and subjected to a hydrogen atmosphere via balloon. The reaction was run overnight and filtered through Celite and concentrated in vacuo to yield tert-butyl (2S)-2-ethylpyrrolidine-1-carboxylate (0.18 g, HPLC RT=3.00 min.). LC-MS m/z (minus t-butyl+CH3CN+1)=185. 1H NMR (CD3OD, 400 Mhz) 3.67-3.63 ppm (m, 1H), 3.36-3.30 (m, 2H), 1.92-1.71 (m, 4H), 1.45 (s, 9H), 1.43-1.29 (m, 2H), 0.90-0.85 (t, 3H).
Reaction SMILES: ClCCl.Cl[C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:18])[C:9]2=[CH:19][S:20][C:21]([CH3:22])=[C:8]12)=[O:6].[CH2:23]([N:25]([CH2:38][CH3:39])[CH2:26][CH2:27][N:28]([CH3:37])[CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]1)[CH3:24]>C(#N)C>[CH2:38]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][N:28]([CH3:37])[CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:18])[C:9]2=[CH:19][S:20][C:21]([CH3:22])=[C:8]12)=[O:6])[CH3:39]
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Reactant: CCN(CC)CCN(C)CCC1CCCCN1
Solvent: ClCCl
Solvent: CC#N
Product: CCN(CC)CCN(C)CCC1CCCCN1C(=O)N1c2ccccc2NC(=O)c2csc(C)c21
Yield: 22 %

Procedure:
Prepared analogously to Example 4, but using dichloromethane instead of acetonitrile as solvent, from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[2-[[2-(diethylamino)ethyl]methylamino]ethyl]piperidine (b.p.0.3 mmHg 92°-95° C.) in a yield of 22% of theory. Colourless crystals, m.p. 131°-133° C. (acetonitrile).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[N:3]=1.[CH2:10]1[C:13]2([CH2:16][CH2:15][CH2:14]2)[CH2:12][N:11]1[CH2:17][CH2:18][OH:19]>>[Br:1][C:2]1[N:3]=[C:4]([CH2:8][O:19][CH2:18][CH2:17][N:11]2[CH2:12][C:13]3([CH2:16][CH2:15][CH2:14]3)[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCN1CC2(CCC2)C1
Reactant: BrCc1cccc(Br)n1
Product: Brc1cccc(COCCN2CC3(CCC3)C2)n1

Procedure:
The title compound was prepared according to Example 251, Step 1 using 2-bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (200 mg, 0.80 mmol) and 2-(2-azaspiro[3.3]hept-2-yl)ethanol (112 mg, 0.80 mmol) as the starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:31]=[C:32]3[C:36](=[C:37]([CH3:39])[CH:38]=2)[N:35]([CH3:40])[CH2:34][C:33]3([CH3:42])[CH3:41])=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([C:30]5[CH:31]=[C:32]6[C:36](=[C:37]([CH3:39])[CH:38]=5)[N:35]([CH3:40])[CH2:34][C:33]6([CH3:42])[CH3:41])=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1N(C)CC2(C)C
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)C(C)(C)CN5C)ncn3)CC1)C(=O)N2
Temperature: 40 °C
Reaction time: 8 h

Procedure:
48 mg (0.17 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 55 mg (0.17 mmol) (6-chloro-pyrimidin-4-yl)-(1,3,3,7-tetramethyl-2,3-dihydro-1H-indol-5-yl)-methanone and 0.050 mL (0.29 mmol) DIPEA were combined in 2 mL DMF and stirred overnight at 40° C. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.