Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:34][C:35]1[N:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)[C:42]2[C:37](=[CH:38][C:39]([C:52](O)=[O:53])=[CH:40][CH:41]=2)[N:36]=1.Cl.[NH2:56][CH:57]1[C:66]2[CH:65]=[C:64]([O:67][CH2:68][C:69]3[CH:70]=[C:71]([CH:74]=[CH:75][CH:76]=3)[C:72]#[N:73])[CH:63]=[CH:62][C:61]=2[CH2:60][CH2:59][CH2:58]1>CN(C)C=O>[NH2:34][C:35]1[N:44]=[C:43]([N:45]2[CH2:46][CH2:47][N:48]([CH3:51])[CH2:49][CH2:50]2)[C:42]2[C:37](=[CH:38][C:39]([C:52]([NH:56][CH:57]3[C:66]4[C:61](=[CH:62][CH:63]=[C:64]([O:67][CH2:68][C:69]5[CH:76]=[CH:75][CH:74]=[C:71]([C:72]#[N:73])[CH:70]=5)[CH:65]=4)[CH2:60][CH2:59][CH2:58]3)=[O:53])=[CH:40][CH:41]=2)[N:36]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: N#Cc1cccc(COc2ccc3c(c2)C(N)CCC3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2nc(N)nc3cc(C(=O)NC4CCCc5ccc(OCc6cccc(C#N)c6)cc54)ccc23)CC1
Reaction time: 2 h
Yield: 79.1 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (20 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 uL, 0.07 mmol) were added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 0.03 mmol) and 3-{[(8-amino-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]methyl}benzonitrile HCl salt (30 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL) at r.t. The reaction was stirred for 2 h. and the product was purified without workup by RP-HPLC (pH=10) to afford the desired compound (0.013 g, 30%) as an amorphous white solid. 1H NMR (400 MHz, DMSO): δ8.84 (d, 1H), 7.77-7.6 (m, 5H), 7.46 (dd, 1H), 7.42 (m, 1H), 6.99 (d, 1H), 6.80 (dd, 1H), 6.74 (m, 1H), 6.36 (bs, 2H), 5.12 (m, 1H), 5.02 (s, 2H), 3.51 (bs, 4H), 3.27 (s, 4H), 2.62 (m, 2H), 2.17 (s, 3H), 1.88 (m, 2H), 1.70 (m, 2H). Analytical LCMS (M+H)+: m/z=548.1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1>>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=3)[CH:10]=2)[C:6]([CH3:14])([CH3:15])[C:7]1=[O:13])[CH3:12]
Reactant: O=C(O)c1cccnc1
Reactant: CCN1C(=O)C(C)(C)c2ccc(N)cc21
Product: CCN1C(=O)C(C)(C)c2ccc(NC(=O)c3cccnc3)cc21

Procedure:
Prepared in analogy to example 17 from 6-amino-1-ethyl-3,3-dimethylindolin-2-one (G. Georges et al., US2006/142247 A1) and nicotinic acid. The title compound was obtained as white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][N:26]=1.C(=O)([O-])O.[Na+]>CC(O)C.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>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=3)[CH:7]=2)=[O:23])[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)O)cn1
Temperature: 90 °C

Procedure:
N-Cyclopropyl-5-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (3.2 g), methyl 6-chloronicotinate (1.73 g), tetrakis(triphenylphosphine)palladium (210 mg) and aqueous sodium hydrogen carbonate (1M, 30 ml) were mixed in propan-2-ol (100 ml) and heated at 90° C. for 18 hours. The reaction was allowed to cool and the propan-2-ol removed under vacuum. The residue was partitioned between ethyl acetate and aqueous sodiumhydrogen carbonate (1M). The aqueous phase was acidified with hydrochloric acid (2N) and extracted with ethyl acetate (×2). The organic extracts were washed with brine, dried (magnesium sulphate) and reduced to dryness under vacuum. The resulting foam was triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}nicotinic acid as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N+:7]([O-])=[CH:6][C:5]=2[N:15]=1.[NH4+:29].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[NH2:29][C:6]1[C:5]2[N:15]=[C:2]([CH3:1])[N:3]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: [NH4+]
Reactant: Cc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of tert-butyl 2-[2-(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (11.21 g, 29.0 mmol) in 75 mL of CH2Cl2 was treated with 75 mL of concentrated NH4OH solution. The mixture was chilled in an ice water bath. To the rapidly stirred mixture was added solid p-toluenesulfonyl chloride (5.53 g, 29.0 mmol) over a 10 min period. The reaction mixture was then warmed to room temperature and treated with 75 mL of CH2Cl2 and 75 mL of water. The organic portion was then washed with 1% Na2CO3 solution (3×) and brine. The organic portion was dried over Na2SO4 and concentrated and triturated in ether to yield 7.13 g of tert-butyl 2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light green solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([NH:10][CH2:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:20]=[C:21]3[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=2)[NH:24][CH:23]=[C:22]3[CH:31]2[CH2:36][CH2:35][N:34]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH2:33][CH2:32]2)[CH:15]=[CH:16][C:17]=1[F:18])[CH3:9].[CH2:42](N)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([NH:10][CH2:11][C:12]2[CH:13]=[C:14]([C:19]3[CH:20]=[C:21]4[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=3)[NH:24][CH:23]=[C:22]4[CH:31]3[CH2:32][CH2:33][N:34]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH2:35][CH2:36]3)[CH:15]=[CH:16][C:17]=2[F:18])[CH2:42][CH2:9]1
Reactant: CCNCc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)ccc1F
Reactant: CCN
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(F)c(CNC5CC5)c4)cc23)CC1
Yield: 49.4 %

Procedure:
The title compound was prepared according to the general procedure of 5-{3-[(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting cyclopropylamine (32 mg, 0.46 mmol) for ethylamine to afford 23 mg of the title compound (49.4%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.C([BH3-])#N.[Na+]>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[NH:3][O:2][CH3:1])=[CH:6][CH:7]=1
Reactant: CON=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONC(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
Reduction of 4,4′-difluorobenzophenone O-methyloxime with sodium cyanoborohydride as described in the preparation of 1-B gave the title hydroxylamine as a clear oil after chromatography on silica gel (elution hexane-dichloromethane 1:1) (41% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.49 (3H, s, OCH3), 5.18 (1H, s, NCH), 5.8 (1H, broad, NH), 7.02 (4H, m, aromatics), 7.35 (4H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 162° C. (dec). Anal. calcd for C14H13F2NO—HCl: C, 58.85; H, 4.94; N, 4.90. Found: C, 59.05; H, 4.74; N, 4.77.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:14](=[O:16])[CH3:15])[N:4]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[S:6][C:5]=12.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([F:26])[CH:25]=1)[CH:21]=O>C1COCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:15][C:14]([C:3]2[N:4]3[C:5]([S:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=43)=[N:1][CH:2]=2)=[O:16])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: CC(=O)c1cnc2sc3c(n12)CCCCC3
Reactant: O=Cc1cc(F)cc(F)c1
Solvent: C1CCOC1
Product: O=C(C=Cc1cc(F)cc(F)c1)c1cnc2sc3c(n12)CCCCC3

Procedure:
1-(6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-ethanone (Formula N-4, 1.8 g in THF (50 mL) was condensed with 3,5-difluorobenzaldehyde according to non-critical variations in PREPARATION 15 to yield pure 3-(3,5-Difluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one (Formula N-5, X=3,5-difluoro), 0.51 g, m.p. 207-209°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[C:12]([O:14]C(=O)C3C=CC=CC=3)([CH3:13])[CH:11]([O:23]C(=O)C3C=CC=CC=3)[CH:10]([CH2:32][O:33]C(=O)C3C=CC=CC=3)[O:9]2)[C:4](=[O:42])[N:3]=1.C(OC(N[C@H](C(O)=O)C(C)C)=O)(C)(C)C.Cl.CN(C)CCCN=C=NCC.CO>ClCCl.CN(C)C1C=CN=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[C:12]([OH:14])([CH3:13])[CH:11]([OH:23])[CH:10]([CH2:32][OH:33])[O:9]2)[C:4](=[O:42])[N:3]=1
Reactant: CC1(OC(=O)c2ccccc2)C(OC(=O)c2ccccc2)C(COC(=O)c2ccccc2)OC1n1ccc(N)nc1=O
Agent: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CC1(O)C(O)C(CO)OC1n1ccc(N)nc1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of compound (5) (58 g, 0.1053 mol) in dichloromethane (500 ml) was stirred at 25° C. under argon atmosphere. N-(tert-butoxycarbonyl)-L-valine (29.7 g, 0.1367 mol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (26.2 g, 0.1367 mol) and 4-(dimethylamino)pyridine (1.3 g, 0.0106 mol) were added and the reaction mixture was stirred at 25° C. and monitored by HPLC (method #2). After 4 hours, HPLC showed 7.9% of starting material. N-(tert-butoxycarbonyl)-L-valine (4.57 g, 0.0210 mol) and 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (4.03 g, 0.0210 mol) were added and stirring was continued at 25° C. for an additional period of 2 hours, after which, HPLC detected 0.7% of starting material. Methanol (60 ml) was added to the reaction mixture and solvents were evaporated under reduced pressure (temperature kept below 40° C.) to give compound (6) as thick oil. This material (93% pure by HPLC/AUC) was used as is for the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH:6]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([NH:16][N:17]=[CH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][C:10]=2[Cl:25])[C:7]#[N:8])=[CH:4][CH:3]=1.[CH3:28][O:29][CH:30]([O:35][CH3:36])[CH2:31][N:32]=[C:33]=[O:34]>C(#N)C.C1CCN2C(=NCCC2)CC1>[CH:18](=[N:17][N:16]([C:12]1[CH:11]=[C:10]([Cl:25])[C:9]([CH:6]([C:7]#[N:8])[C:5]2[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:14]([Cl:15])[CH:13]=1)[C:33]([NH:32][CH2:31][CH:30]([O:35][CH3:36])[O:29][CH3:28])=[O:34])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(CN=C=O)OC
Reactant: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(NN=Cc2ccccc2)cc1Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(CNC(=O)N(N=Cc1ccccc1)c1cc(Cl)c(C(C#N)c2ccc(Cl)cc2)c(Cl)c1)OC
Reaction time: 1 h
Yield: 87.8 %

Procedure:
In 20 ml of acetonitrile was suspended 3.2 g of benzaldehyde 4-(4-chloro-α-cyanobenzyl)-3,5-dichlorophenyl hydrazone. To the suspension were added 1.5 g of 2,2-dimethoxyethyl isocyanate and 20 mg of DBU. The reaction was allowed to proceed for one hour at room temperature, then the resulting crystalline precipitate was collected by filtration, which was washed with hexane, followed by drying to afford 3.7 g of the titled compound as colorless crystals, m.p.190-191° C.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)[CH2:2][CH3:3].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCCC1.C(Cl)Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1)[CH2:2][CH3:3]
Reactant: C#Cc1ccccc1
Reactant: CCCNC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCNCC1
Solvent: O
Solvent: ClCCl
Product: CCCNC(=O)c1cccc(C#Cc2ccccc2)c1
Temperature: 70 °C

Procedure:
A mixture of N-n-propyl-4-bromobenzamide from Example 9A, phenylacetylene (1.5 eq.) and Pd(PPh3)2Cl2 (5 mol %) in piperidine (3 eq.) was heated at 70° C. for 30 minutes in a sealed tube. The solidified residue was dissolved with CH2Cl2 and water and poured onto HCl 2N. The acidic phase was extracted three times with CH2Cl2. The combined organic layers were washed once with HCl 2N, twice with saturated NaHCO3, once with water and once with brine. The organic layer was then dried over MgSO4 and concentrated. The resulting residue was purified using SiO2 with CH2Cl2/petroleum ether 80:20 to CH2Cl2 100% to give N-n-propyl-3-phenylethynyl-benzamide as a yellow solid (Quantitative yield). NMR 1H (ppm, CDCl3): 7.73 (d. J3=8.4 Hz, 2H), 7.63-7.51 (m, 5H), 7.36-7.32 (m, 2H), 6.10 (br. s., 1H), 3.45-3.37 (m, 2H), 1.64 (sext., J=7.2 Hz, 2H), 0.99 (t, J3=7.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@@H:14]([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([CH:28]=O)=[N:22][N:23]([CH:25]([F:27])[F:26])[CH:24]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[Cl:19][C:20]1[C:21]([CH2:28][NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]3([CH3:17])[C@@H:14]([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9]3)[CH:7]=2)=[N:22][N:23]([CH:25]([F:27])[F:26])[CH:24]=1
Reactant: O=Cc1nn(C(F)F)cc1Cl
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COC[C@@H]1F
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: C[C@]1(c2cc(NCc3nn(C(F)F)cc3Cl)ccc2F)N=C(N)COC[C@@H]1F
Temperature: 23 °C
Reaction time: 1 h
Yield: 4.5 %

Procedure:
To a solution of (5R,6R)-5-(5-amino-2-fluoro-phenyl)-6-fluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylamine (intermediate A10B) (20.4 mg, 80 μmol) in methanol (0.3 ml) was added at 23° C. under inert atmosphere 4-chloro-1-difluoromethyl-1H-pyrazole-3-carbaldehyde (15.9 mg, 88 μmol) and the reaction mixture was stirred at 23° C. for 60 min. Then decaborane (19.5 mg, 160 μmol) was added in one portion and the mixture was stirred at 45° C. for 15 h. The solution was quenched with 10% Na2CO3-sol., methanol was removed under reduced pressure and then extracted three times with ethyl acetate. The organic layers were dried with Na2SO4 and evaporated to give the crude product, which was purified by basic preparative HPLC (column: Gemini 5μ C18 110A° AXIA (50×21.2 mm), flow: 40 ml/min; gradient: water (+0.1% TEA)/acetonitrile (90%-10% 1 min plateau; in 4.5 min to 5%-95%); collection: UV-detector 230 nm) and further purified by preparative TLC (Merck Si—NH2 HPTLC-plate with dichloromethane/methanol 9:1) to give the (5R,6R)-5-(5-((4-chloro-1-(difluoromethyl)-1H-pyrazol-3-yl)methylamino)-2-fluorophenyl)-6-fluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (1.5 mg, 4.5%) as a colorless oil. MS (ISP): m/z=420.1 [(M+H)+] and 422.1 [(M+2+H)+].
Reaction SMILES: [ClH:1].[C:2]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:18](C)=O.[Na+].CC(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[ClH:1].[CH3:18][N:11]1[CH2:10][CH2:9][CH:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.2 %

Procedure:
A mixture of 4-phenyl piperidine hydrochloride (1.23 g, 6.2 mmol), formaldehyde (36.5% in H2O, 0.702 ml, 9.3 mmol), NaBH(OAc)3 (2.63 g, 12.42 mmol) and AcOH (0.71 ml, 12.42 mmol) in DCM (30 ml) was stirred for 24 hours at room temperature. The mixture was then brought to basic conditions with a 5% NaHCO3 solution and extracted twice with DCM. The pooled organic phases were dried over Na2SO4 and evaporated to dryness. The residue was dissolved in DCM and treated with HCl in Et2O observing the precipitation of a white solid. The solid was filtered off through a Buchner funnel to obtain 1 g of 1-methyl-4-phenylpiperidine hydrochloride as a white solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[N:11]=[C:10]([C:37]([OH:39])=[O:38])[N:9]=1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([S:24]([NH:23][C:12]2[N:11]=[C:10]([C:37]([OH:39])=[O:38])[N:9]=[C:8]([O:7][CH2:6][CH2:5][OH:4])[C:13]=2[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)(=[O:25])=[O:26])=[CH:32][CH:31]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(C(=O)O)nc2OCCOC(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(C(=O)O)nc2OCCO)c1
Yield: 40.8 %

Procedure:
0.09 g of 4-(2-acetoxy-ethoxy)-6-(4-tert.butyl-phenyl-sulphonylamino)-5-(3-methoxy-phenoxy)-pyrimidine-2-carboxylic acid in 4 ml of methanol and 1.5 ml of water was stirred with 0.05 g of sodium carbonate at 20° C. for 2 hours. The methanol was evaporated and the residue was partitioned between chloroform and aqueous 1N hydrochloric acid. The organic phase was dried and evaporated. The residue was purified over silica gel with chloroform-methanol-water, 60:35:5. There was obtained 0.034 g of 6-(4-tert.butyl-phenylsulphonylamino)-4-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-pyrimidine-2-carboxylic acid, MS: (M-H)- 515.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4]P(OCC(F)(F)F)(OCC(F)(F)F)=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:30][C:31]1[CH:32]=[C:33]([CH:36]=O)[S:34][CH:35]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O.O>[CH3:1][O:2][C:3](=[O:19])[CH:4]=[CH:36][C:33]1[S:34][CH:35]=[C:31]([Br:30])[CH:32]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C=Cc1cc(Br)cs1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
[Bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acid methyl ester (9.25 g, 29.1 mmol) was dissolved in THF (400 ml) and 18-C-6 (13.9 g, 52.4 mmol) was added and the mixture was cooled to −78° C. Next, KHMDS (5.73 g, 28.8 mmol) was added and the reaction mixture was stirred for 30 minutes, after which 4-bromothiophene-2-carboxaldehyde (5.0 g, 26.2 mmol) was added and the reaction was stirred for an additional 3 hours. Saturated NH4Cl (100 ml) was added and the reaction was warmed to 22° C. The mixture was diluted with EtOAc (700 ml) and H2O (400 ml). The organic layer was washed 10% HCl (100 ml), brine (100 ml), and dried (MgSO4). The solvent was evaporated in vacuo and the crude residue was purified by silica-gel chromatography (hexanes:EtOAc-10:1) providing 5.6 g (87%) of the subtitle product.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][C:7](=[O:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[CH2:16](Br)[C:17]#[CH:18].C1(C)C=CC=CC=1>CCOCC.C1COCC1>[CH:3]1([N:6]([CH2:18][C:17]#[CH:16])[C:7](=[O:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:5]1
Reactant: O=C(Cc1ccccc1)NC1CC1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C#CCN(C(=O)Cc1ccccc1)C1CC1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 58.8 %

Procedure:
Sodium hydride (60% in mineral oil, 706 mg, 17.65 mmol) was washed with dry ether (2×20 mL) and then suspended in dry THF (30 mL) and cooled with ice-water. Crude N-cyclopropyl-2-phenylacetamide from the last step in THF (5 mL) was added dropwise at 5° C. to the sodium hydride suspension. The reaction mixture was stirred at 5° C. for 20 min. A solution of propargyl bromide in toluene (80% wt., 2.68 mL, 24.06 mmol) was added dropwise with a syringe. The ice bath was removed and the mixture was stirred at room temperature overnight. The mixture was poured into ice-water (100 mL) and extracted with DCM (3×100 mL). The organic phases were combined and washed with brine (2×50 mL), dried with anhydrous MgSO4, filtered and evaporated to dryness, then purified by silica gel column chromatography, eluting with MeOH/DCM (0-2%) to give the title compound (2.05 g, 58.8% yield), LRMS ESI (M+H+) 214.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:14](=[O:23])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[CH:37]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:38]([O:40][CH3:41])=[O:39].O>CN(C=O)C.C(Cl)Cl>[CH3:41][O:40][C:38](=[O:39])[CH:37]([N:27]1[CH2:28][CH2:29][CH:24]([N:13]([C:10]2[CH:11]=[C:12]3[C:7]([CH2:6][CH2:5][N:4]3[C:1](=[O:3])[CH3:2])=[CH:8][CH:9]=2)[C:14](=[O:23])/[CH:15]=[CH:16]/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:25][CH2:26]1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC(=O)N1CCc2ccc(N(C(=O)/C=C/c3ccccc3)C3CCNCC3)cc21
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(c1ccccc1)N1CCC(N(C(=O)/C=C/c2ccccc2)c2ccc3c(c2)N(C(C)=O)CC3)CC1
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of trans-N-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-3-phenyl-N-piperidin-4-yl-acrylamide (Example 41, Step C; 49 mg, 0.13 mmol) in DMF (0.5 mL) and DCM (2 mL) was added Na2CO3 (41 mg, 0.39 mmol) followed by methyl α-bromophenylacetate (26 μL, 0.16 mmol). After stirring overnight, the reaction mixture was poured into H2O and DCM was added. The organic fraction was washed with brine (3×), dried (Na2SO4), and concentrated. Purification by silica gel chromatography (2% methanol (2 M NH3) in DCM) afforded 59 mg (84%) of the title compound. 1H NMR (400 MHz, CDCl3): 8.04 (br d, J=12.4 Hz, 1H), 7.62 (d, J=15.4 Hz, 1H), 7.38-7.22 (m, 10H), 7.18 (dd, J=8.8, 8.0 Hz, 1H), 6.73 (dd, J=17.2, 7.8 Hz, 1H), 6.15 (d, J=15.6 Hz, 1H), 4.74 (br dd, J=12.4, 12.1 Hz, 1H), 4.17 (dd, J=8.8, 8.3 Hz, 2H), 3.94 (d, J=3.8 Hz, 1H), 3.65 (s, 3H), 3.31-3.24 (m, 2H), 3.01-2.94 (m, 1H), 2.76-2.69 (m, 1H), 2.34-2.22 (m, 1H), 2.24 (d, J=5.3 Hz, 3H), 2.02-1.76 (m, 2H), 1.76-1.63 (m, 1H), 1.61 (s, 3H), 1.58-1.40 (m, 1H). MS: exact mass calculated for C33H35N3O4, 537.3; m/z found, 538.5 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[N:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:49]3[CH2:50][CH2:51][N:46]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][N:40]=4)[CH2:47][CH2:48]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: c1ccc(N2CCNCC2)nc1
Product: Cc1ccccc1-c1nc(N2CCN(c3ccccn3)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 97.3 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 1-(pyridine-2-yl)piperazine (29.4 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-[4-(pyridine-2-yl)piperazine-1-yl]pyrimido[4,5-b][1,5]diazocine (95.7 mg, 97%).